UNIVERSITY OF SOUTH FLORIDA BOARD OF TRUSTEES v. USA

REPLY to Response to Motion re MOTION for Partial Summary Judgment '094 Patent Claims are entitled to Benefit of the 10-21-96 Filing Date

Fed. Cl.March 15, 2019

THE UNITED STATES COURT OF FEDERAL CLAIMS UNIVERSITY OF SOUTH FLORIDA, BOARD OF TRUSTEES, Plaintiff, v. THE UNITED STATES OF AMERICA, Defendant. ) ) ) ) ) ) ) ) ) ) No. 15-1549 Judge Campbell-Smith USF REPLY TO THE OPPOSITION OF THE UNITED STATES TO USF’S MOTION FOR PARTIAL SUMMARY JUDGMENT – THE ‘094 PATENT IS ENTITLED TO AN EFFECTIVE DATE OF OCTOBER 21, 1996 The Government has conceded that the invention claimed in U.S. Patent No. 5,898,094 (hereinafter “the ‘094 Patent”) is disclosed and described in accordance with the requirements of the governing statute, 35 U.S.C. §112, first paragraph. See, ECF 129, p. 1: “Having reviewed USF’s Motion, and upon further investigation of the evidentiary record, the Government will no longer pursue this invalidity defense against Claims 7-8 and 10-11 under Section 112, First Paragraph.” Yet, the Government takes the position that the exact same invention is not disclosed in accordance with the exact same statute by the properly referenced U.S. Provisional Patent Application Serial No. 60/028,937 (hereinafter “the ‘937 Application”) – opposing USF’s Motion for Summary Judgment that the ‘094 Patent is entitled to the filing date of October 21, 1996. The only difference between the ‘937 Application disclosure and the ‘094 Patent disclosure is the Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 1 of 13 2 absence, in the ‘937 Application, of the specific mouse examples, which of course had not yet been bred. This is a slender reed for opposition, given the widely recognized proposition that “there is no requirement that the disclosure contains either examples or an actual reduction to practice.” Alcon Research Ltd., v. Barr Labs, Inc. 745 F. 3d 1180, 1191 (Fed. Cir. 2014). In point of fact, boiled down to its essentials, the Government’s Opposition urges the position that the ‘937 Application neither describes use of the Swedish mutation as the APP mutation called for by the claims (APP K670N, M671L) nor enables its use in the mice claimed in the ‘094 Patent. Opp. p. 5. This is the Government’s position, notwithstanding the Government’s acknowledgement in the very next sentence that in fact the ‘937 Application does “reference a 1996 Hsiao Article that discloses an APPswe mouse.” Both things cannot be true – either the ‘937 Application does not refer to a mouse that is the APPswe mouse, or it does. Since every witness that was asked – Duff, Borchelt, Snyder - testified that in fact the Hsiao article that is referenced on page 3 of the provisional ‘937Application did in fact disclose the APPswe mutation, there can be no question that it was in fact described as called for by Statute. Snyder, Ex. 3, 42:20 – 44:6. The Government’s position that somehow pinpointing this mutation as a suitable APPswe mutation is insufficient to describe it, or that directing one to cross-breed that mouse with another reflecting a presenilin mutation is somehow Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 2 of 13 3 not enabling, is not only not supported by evidence, it is contrary to the testimony of the witness the Government relies on for lack of invention – David Borchelt. The testimony of Borchelt, Ex. 2, p. 72:2 – 73:3 and Duff, Ex. 1, 211: 2–24, is discussed in detail below. USF replies herewith to the Government’s Opposition. I. THE ‘937 APPLICATION DESCRIBES USING THE SWEDISH MUTATION The central teaching of the ‘937 Application appears at page 8 (Ex. 11): Consequently, one object of the present invention involves producing animal models for Alzheimer's disease by crossing a transgenic animal containing within its genome at least one copy of an expressible variant of a wildtype or mutant mammalian APP transgene within its genome with a transgenic animal containing within its genome at least one copy of an expressible mutant variant of a wild type or mutant mammalian presenilin gene to produce as offspring containing within its genome at least one copy of an expressible variant of a wild type or mutant APP transgene and at least one copy of an expressible variant of a wild type or mutant presenilin. The ‘937 Application identifies three possible “mutant mammalian APP transgenes” for use in the invention. The first two are noted at page 3, where the ‘937 Application teaches the reader: In an effort to develop animal models to study pharmaceutical agents designed to treat FAD, transgenic mice have been developed containing the missense point mutations of the human APP gene in their genome. Hsiao et al, Science 274:99 (1966) and Games et al, Nature 373:523 (1995)). At page 11, the ‘937 Application identifies a third APP mutation that might be used in the disclosed invention. Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 3 of 13 4 The production of a transgenic mice containing within its genome at least one copy of an expressible wildtype or mutant mammalian APP transgene is (sic, in) its genome is in the prior art. An example of such production is disclosed in U.S. Patent #5,387,742 (Cordell, B.) which is incorporated by reference herein and attached hereto as Appendix C. (emphasis supplied). The ‘937 Application then made clear that any one of the three APP mutations identified, or indeed any other APP mutation, could be used to make the doubly transgenic mice of the invention. The next line reads: However, applicants believe any presently known or subsequently discovered mutations in the human APP gene responsible for Alzheimer’s pathology can be used. It would be hard to be more clear – at a minimum, the ‘937 Application teaches that you can use the Swedish mutation of Hsiao, the APP mutation of Games, or the APP mutation of Cordell to provide the mouse expressing the APP transgene of the invention.1 While the Government repeatedly asserts that USF relies on the description of a genus to satisfy claims that are drawn to a species, Opp., p. 19, in fact the Government has it upside down. USF specifically relies on the unquestioned identification, in the ‘937 Application, of the mouse disclosed in Hsiao et al, Science 274:99 (1966) as one of three candidate species. This mouse reflects the APP K670N, M671L transgene recited in the claims. Had the ‘094 Patent claims 1 The mice of Hsiao, Games and Cordell all express APP transgenes of differing identity and sequence. Some were not available to Duff and Hardy at the time of their invention. Ex. 1, 66:7–16. Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 4 of 13 5 been confined to an APP mutation that was NOT identified in the ‘937 Application, and one that could not have been predicted for some reason, then the Government’s argument would have some weight – but that is not the case. The ‘937 Application identifies three APP transgenes as suitable for use, and the ‘094 Patent confines its claims to one of those three transgenes. It is not a violation of the written description requirement to describe multiple inventions in a patent specification if you claim only one of those described. The Federal Circuit’s landmark decision on written description, Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co. 598 F.3d 1336, 1350 (Fed Cir. 2010) (en banc) made it clear that a specific, complete description of that which is claimed satisfies the written description requirement: We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed.Cir.1993)). Here – the ‘937 Application identifies the one and only species at issue by name and provides full disclosure of the mice and mutation in question. The Hsiao article in question is Ex. 13. It identifies the precise mutation in question, how it was introduced into the mice, and the characteristics of the resulting singly transgenic mice. The claims of the ‘094 Patent, with respect to the APP transgene – have no generic scope – they recite, in each and every claim, the species of APP transgene Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 5 of 13 6 required – the APPswe transgene. That same transgene is identified in the ‘937 Application. It is fully described. The Government’s sole basis for Opposing Summary Judgment on the grounds of lack of written description seems to be that the words “APPswe mutation” do not appear, ipsis verbis, in the ‘937 Application. This is not a reasonable position – the application describes the very specific transgenic mice in terms no one questions. The specific name APPswe is not required. Nor was an actual example required – Falko Gunter v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006). Indeed, this case aligns with Inglis almost exactly. Borchelt, the Government’s own witness, testified that in fact the Hsiao article was known and part of the prior art by October, 1996 when the ‘937 Application was filed, Ex. 2, p. 72:2 – 73:3, and he confirmed that the article referenced discloses the APPswe mutation. Ex. 2, 72:13–15 (Q. And that refers to a transgenic mouse with the Swedish mutation. Is that accurate? A. Yep, yep. ) Duff said the same thing. Ex. 1, 211: 2–24. Compare this with the Federal Circuit’s observation in Inglis at 1366: Furthermore, the testimony of Inglis' expert, Dr. Boursnell, established that the articles describing essential genes for poxvirus were well-known in the art. Dr. Boursnell testified that “the skilled person would have been readily able to choose an essential vaccine gene based on references that have been publicly available since 1990. Importantly, there is no need to explain in detail that which is known in the prior art. Spectra-Physics,Inc. v. Coherent, Inc. ,827 F.2d 1524, 1534 (Fed. Cir. 1987). Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 6 of 13 7 Thus, like the thirty (30) presenilin mutations known to those of skill in the art as of 1996 courtesy of the Cruts et al publication (Ex. 12 hereto), all that was necessary to meet the written description requirement was to specifically identify the Hsiao et al mouse reflecting the APPswe transgene and to provide instructions to crossbreed the two mice. The ‘937 Application does this precisely. Anyone of skill in the art, reading the ‘937 Application, would know that Hsiao et al describes the precise transgenic mouse with the precise transgene recited in the claims of the ‘094 Patent, and readily recognize that is one of the candidate mutations identified in the application that might be used. Where, as here, the claim scope with respect to the recited APP mutation matches precisely the disclosure of the’937 Application (use the Hsiao et al APP mouse) there can be no question that written description is satisfied. II. THE ‘937 APPLICATION ENABLES THE CLAIMED INVENTION At pages 22–23 of its Opposition to USF’s Motion for Summary Judgment that it is entitled to the October 21, 1996 filing date of the ‘937 Provisional Application, the Government appears to take USF to task for two items – one, failing to apply the “Wands factors” to enablement of the’937 Application and two, relying on testimony that does not appropriately reflect someone of ordinary skill in the art as of 1996 to explain what the ‘937 Application taught. Both arguments fall wide of the mark. Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 7 of 13 8 USF’s Motion for Summary Judgment made the point that with respect to enablement – NO undue experimentation, or indeed, experimentation of any kind, was required. SOMF 14 and 17–19, pp. 7–9 and Argument, pp. 9-11. Provided one used the very specific APPswe mutation identified, and any presenilin mutation, accelerated Alzheimer’s Disease related pathology in the offspring mice would be observed. This was Borchelt’s testimony – Ex, 2, 90:14-22; 68:11 – 69:17. “Q. In your experience, and that can be up through today, if combined with…this APP –Swedish mutation, do most of the presenilin mutations give you a similar result? A. All of the ones I am aware of that have been tested give the same result.” Duff testified in the same fashion. Ex. 1, 81:12 – 82:9. Accordingly, this is one of those rare inventions in the biological sciences that works every time. Thus, there is no point to exploring the issue addressed in In re Wands, 858 F. 2d 731, 737 (Fed. Cir. 1988). Indeed, the Court made unpredictability a predicate of its decision in Wands, at 734: The position of the PTO is that data presented by Wands show that the production of high-affinity IgM anti–HBsAg antibodies is unpredictable and unreliable, so that it would require undue experimentation for one skilled in the art to make the antibodies. Here, the preparation of mice with accelerated Alzheimer’s Disease related pathology using a mouse that reflects the APPswe mutation, as described in the Hsiao et al article that is Ex. 13, and a mouse that reflects any presenilin mutation is 100% percent predictable – it ALWAYS yields accelerated pathology. Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 8 of 13 9 The Government’s position is that David Borchelt’s testimony acknowledging that the ‘937 Application teaches one of skill in the art precisely how to prepare the invention claimed in the ‘094 Patent – Ex. 2, 71:13 – 73:10 and 82:1 – 89:21 is not appropriate because he had greater skill than those in the art. Opp., pp. 22-23. The Government is wrong at several levels, but it’s noteworthy first to understand precisely what Dr. Borchelt said in reviewing the “937 Application at Ex. 2, 89:12-21: Q. So whether you used the Cordell mouse, or the Hsiao mouse, or the Gaines mouse— A. Right. Q. – The patent is telling you to put –or the provisional application, this is not a patent—is telling you to do something analogous to what you and your co-researchers did, that is crossing the APP mouse and a presenilin mutation. Is that generally accurate? A. Yep. That’s what it looks like. Borchelt went page by page, line by line, through the provisional application and concluded it taught exactly what is claimed in the ‘094 Patent- a method to make mice that exhibit an APPswe mutation and a presenilin mutation – which will yield accelerated Alzheimer’s Disease related pathology, and the resulting mice. The Government suggests this is not appropriate, as it relies on Dr. Borchelt’s understanding, not those of ordinary skill in the art. In so arguing, the Government ignores Dr. Borchelt’s own characterization of the level of skill in the art in 1996. Borchelt was asked to characterize what the educational and Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 9 of 13 10 experience background would have been of someone working in the field of transgenic mice by the end of 1966. Ex. 2, 75:16–21. Dr. Borchelt answered precisely the way you would expect, Ex. 2, 76:2-19: All the authors on the team involved in producing these animals would be led by someone with a Ph. D. Dr. Borchelt continued to describe a team with no less than six Ph.D.’s and some post-doctoral candidates. Indeed, Dr. Borchelt’s ex parte Declaration makes it clear that he is an example of such a team leader. Ex. 31, ¶¶ 2–3. In describing the work that was done under the leadership of himself and others, Borchelt NEVER refers to the work he did alone, he always refers to efforts of his “research group.” See, ¶¶ 5, 6, 8, 9, 10 and 14, as well as the references in ¶¶ 11, 12 and 13, which refer to “our double transgenic mice, our grant submission and our 1997 article.” (Emphasis supplied). Dr. Borchelt is not the first scientist to ever be in a discipline where research is conducted by a group, and the level of skill in the art is reflected by the level of skill in the group as a whole. Pfizer, Inc. v. Genentech, Inc. , 2018 WL 1313426 *4 (PTAB) and Apotex, Inc. v. Novartis AG, 2017 WL 306797 *4 (PTAB): On the record before use, we find that one of ordinary skill in the art may be part of a multi-disciplinary research team including a 1) Ph. D. with expertise in the area of neurology and/or MD having several years of clinical experience… This approach is echoed in case after case involving modern research into complex technologies: Nippon Suisan Kaisha, Ltd. v. Pronova Biopharma Norge, 2018 WL Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 10 of 13 11 456352 *3 (PTAB 2018), Hospira v. Genentech, 2017 WL 3209401 *3 (PTAB). Thus, one of ordinary skill in this art would reflect the skill of the team, which would include the Ph.D education. and experience, of someone like David Borchelt as team leader. Sandoz, Inc. v. AbbVie Biotechnology, Inc., 2018 WL 2735648 *3 (PTAB): We consider the asserted grounds of unpatentability in view of the understanding of a person of ordinary skill in the art...A person of ordinary skill in the art would have the skill sets of a team comprising a pharmacologist having experience with TNFα inhibitors and a physician treating patients for Inflammatory Bowel Disease (IBD), including Crohn’s disease and ulcerative colitis… In Sandoz, like the other cases cited, the Board adopted the argument that the hypothetical person of skill in the art would have reflected a team having the knowledge of its leaders. As in all the cases discussed above, the level of skill in the art is that which would be held by a team of qualified individuals led by those having a high level of skill in the art. Dr. Borchelt was in fact one such leader. The team benefits from, and reflects, all the knowledge held by its team members. The Government nowhere suggests an alternative definition of the level of skill in the art. As Dr. Borchelt testified, those of skill in this art, operating as a team, would have understood the ‘937 Application to be directing those of skill in the art to cross a mouse having a presenilin mutation (of which there were at least 30 known in the art) with a mouse having an APPswe mutation (which was also available in Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 11 of 13 12 the art). Doing so, as both Borchelt and Duff testified, gives you offspring mice which exhibit accelerated Alzheimer’s Disease related pathology as this Court has construed that term, no matter which presenilin mutation is selected. The invention claimed in the ‘094 patent is clearly enabled by the ‘937 Specification. III. CONCLUSION The ‘937 Application, Ex. 11, directs one of skill in the art to use an APP mutation-bearing mouse as one parent of the mice to be prepared. It identifies three different possibilities – the mice disclosed by Hsiao et al, Science 274:99 (1966); those disclosed by Games et al, Nature 373:523 (1995) and those set forth by Cordell (U.S. Patent No. 5,387,742). Ultimately, the ‘094 Patent issued with claims confined to an exact APP mutation parent identified in the ‘937 Application – the APPswe parent of Hsiao et al. The ‘937 Specification specifically described cross- breeding that mouse with one with a presenilin mutation. In October of 1996, no one had yet prepared and measured such mice. But the techniques identified and required were not new – Borchelt, whose experience and qualifications are reflective of the kind of group that was engaged in this research at the time, so testified. And stunningly, when the results were obtained, and repeated for a period of over twenty years, that very specifically disclosed invention – cross-breeding an APPswe mouse with one exhibiting a presenilin mutation, gives offspring who always exhibit accelerated Alzheimer’s Disease Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 12 of 13 13 related pathology, as recited by the ‘094 Patent claims. There is no issue of “undue experimentation” – it works every time. Where the elements of the claims of the issued patent are specifically identified in the Provisional Application, and the instructions provided in the specification to use those elements provide the sought after result every time, the invention is both described and enabled. The Government concedes that the ‘937 Application otherwise meets the test for a constructive reduction to practice. USF respectfully requests grant of its Motion for Partial Summary Judgment that the ‘094 Patent is entitled to benefit of the October 21, 1996 filing date of the ‘937 provisional application. Dated: March 15, 2019 OF COUNSEL: Jerry Stouck Email: stouckj@gtlaw.com GREENBERG & TRAURIG 2101 L Street, N.W., Suite 1000 Washington, DC 20037 (202) 331-3173 phone (202) 261-4751 facsimile s/Steven B. Kelber Steven B. Kelber Email: steve@kelberlawgroup.com THE KELBER LAW GROUP 1875 Eye Street, N.W., Fifth Floor Washington, D.C. 20006 240-506-6702-Telephone Counsel for Plaintiff University of South Florida, Board of Trustees Case 1:15-cv-01549-PEC Document 135 Filed 03/15/19 Page 13 of 13