UNIVERSITY OF SOUTH FLORIDA BOARD OF TRUSTEES v. USARESPONSE to 117 MOTION for Partial Summary Judgment '094 Patent Claims are not Invalid for Prior InventorshipFed. Cl.February 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 Patricia Campbell-Smith DEFENDANT’S OPPOSITION TO MOTION BY USF FOR PARTIAL SUMMARY JUDGMENT—U.S. PATENT NO. 5,898,094 IS NOT INVALID BY REASON OF PRIOR INVENTORSHIP 35 U.S.C. § 102(g) JOSEPH H. HUNT Assistant Attorney General GARY L. HAUSKEN Director WALTER W. BROWN Senior Litigation Counsel Commercial Litigation Branch Civil Division Department of Justice Washington, D.C. 20530 walter.brown2@usdoj.gov Telephone: (202) 307-0341 Facsimile: (202) 307-0345 February 15, 2019 Attorneys for the United States Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 1 of 42 i TABLE OF CONTENTS Table of Contents ............................................................................................................................. i Table of Authorities ........................................................................................................................ ii I. Summary of Argument ........................................................................................................... 1 II. Counterstatement of Facts....................................................................................................... 3 A. Government’s Responses to USF’s Statement of Material Facts ........................... 3 B. Government’s Asserted Material Facts ................................................................. 11 1. Borchelt Group Research .......................................................................... 11 2. Further Research Leading to the 1997 Neuron Article ............................. 15 3. Further Research Leading to the 1996 Neuron Article ............................. 16 4. Hardy/Duff Research ................................................................................ 18 III. Argument .............................................................................................................................. 20 A. Legal Standards ..................................................................................................... 20 1. Summary Judgment Standard ................................................................... 20 2. Defenses under Pre-AIA 35 U.S.C. § 102(g) ............................................ 21 B. The Government’s Contentions ............................................................................ 21 C. Proving Prior Inventorship Requires Corroborating Evidence. ............................ 24 D. USF Wrongly Asserts that Dr. Borchelt Did Not “Appreciate” His Invention at the Time of His Group’s Alleged Conception. ................................................. 26 E. Dr. Borchelt Conceived His Double-Transgenic Mice in 1995, with the First Mice Born in April 1996. ...................................................................................... 30 F. There is No Evidence that Dr. Borchelt Had a Conflict of Interest. ..................... 32 G. Dr. Borchelt’s Group Then Diligently Pursued Its Conceived Mouse Model to a Reduction to Practice. .................................................................................... 33 H. USF’s Purported 1995 Conception Lacks Any Corroborating Evidence. ............ 34 I. The Hardy/Duff Group’s Earliest Research Benchmarks Repeatedly Occurred Significantly After the Borchelt Group’s Work. ................................................... 35 IV. Conclusion ............................................................................................................................ 36 Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 2 of 42 ii TABLE OF AUTHORITIES Cases Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200 (Fed. Cir. 1989)......................................................................................... 30 Anderson v. Liberty Lobby, Inc., 477 U.S. 242 (1986) .......................................................................................................... 20 Apotex USA, Inc. v. Merck & Co., Inc., 254 F.3d 1031 (Fed. Cir. 2001)......................................................................................... 26 Berry v. Webb, 412 F.2d 261 (C.C.P.A. 1969) .......................................................................................... 24 Brown v. Barbacid, 436 F.3d 1376 (Fed. Cir. 2006)......................................................................................... 24 Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223 (Fed. Cir. 1994)..................................................................................... 26, 30 Celotex Corp. v. Catrett, 477 U.S. 317 (1986) .......................................................................................................... 20 Coleman v. Dines, 754 F.2d 353 (Fed. Cir. 1985)........................................................................................... 24 Cooper v. Goldfarb, 154 F.3d 1321 (Fed. Cir. 1998)......................................................................................... 25 Dow Chem. Co. v. Astro-Valcour, Inc., 267 F.3d 1334 (2001) ........................................................................................................ 26 Eibel Process Co. v. Minn. & Ont. Paper Co., 261 U.S. 45 (1923) ............................................................................................................ 24 Field v. Knowles, 183 F.2d 593 (C.C.P.A. 1950) .......................................................................................... 24 Fiers v. Revel, 984 F.2d 1164 (Fed. Cir. 1993)................................................................................... 30, 32 Heard v. Burton, 333 F.2d 239 (C.C.P.A. 1964) .......................................................................................... 26 Hitzeman v. Rutter, 243 F.3d 1345 (Fed. Cir. 2001)......................................................................................... 26 Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 3 of 42 iii In re Jolley, 308 F.3d 1317 (Fed. Cir. 2002)......................................................................................... 24 Kimberly-Clark Corp. v. Johnson & Johnson, 745 F.2d 1437 (Fed. Cir. 1984)......................................................................................... 25 Kridl v. McCormick, 105 F.3d 1446 (Fed. Cir. 1997)......................................................................................... 24 Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572 (Fed. Cir. 1996)..................................................................................... 24, 26 Matsushita Elec. Indus. Co. v. Zenith Radio Corp., 475 U.S. 574 (1986) .......................................................................................................... 21 Monsanto Co. v. Mycogen Plant Sci., Inc., 261 F.3d 1356 (Fed. Cir. 2001)....................................................................... 24, 25, 33, 34 Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316 (Fed. Cir. 2001)......................................................................................... 21 Perfect Surgical Techniques, Inc. v. Olympus Am., Inc., 841 F.3d 1004 (Fed. Cir. 2016)......................................................................................... 34 Price v. Symsek, 988 F.2d 1187 (Fed. Cir. 1993)......................................................................................... 24 Rines v. Morgan, 250 F.2d 365 (C.C.P.A. 1957) .......................................................................................... 25 Silvestri v. Grant, 496 F.2d 593 (C.C.P.A. 1974) .......................................................................................... 26 Singh v. Brake, 317 F.3d 1334 (Fed. Cir. 2003)......................................................................................... 25 Stamps.com Inc. v. Endicia, Inc., 437 Fed. Appx. 897 (Fed. Cir. 2011) ................................................................................ 26 Teva Pharm. Indus. Ltd. v. AstraZeneca Pharms. LP, 661 F.3d 1378 (Fed. Cir. 2011)................................................................................... 25, 33 Tyco Healthcare Grp. v. Ethicon Endo-Surgery, Inc., 774 F.3d 968 (Fed. Cir. 2014)........................................................................................... 25 United States v. Diebold, Inc., 369 U.S. 654 (1962) .......................................................................................................... 21 Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 4 of 42 iv Statutes 35 U.S.C. § 102 ............................................................................................................. 1, 11, 21, 23 35 U.S.C. § 103 ............................................................................................................................. 23 Rules RCFC 56 ............................................................................................................................. 3, 11, 20 Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 5 of 42 1 Defendant, the United States of America (the government), hereby respectfully submits its response in opposition to Plaintiff, University of South Florida Board of Trustees’ (USF’s), Motion for Partial Summary Judgment that U.S. Patent No. 5,898,094 (the ’094 patent) Is Not Invalid for by Reason of Prior Inventorship (Dkt. No. 117). Pursuant to the Court’s Order of January 30, 2019, Dkt. No. 127, this opposition brief is timely filed. I. SUMMARY OF ARGUMENT In its motion, USF seeks to destroy key government invalidity defenses under 35 U.S.C. § 102(g) without properly considering the law of inventorship and by ignoring numerous factual issues surrounding the asserted dates of invention by the research teams of (1) Dr. David Borchelt (relied upon by the government) and (2) Drs. John Hardy and Karen Duff, the named inventors of the ’094 patent (relied upon by USF). When the legal requirements of corroboration and appreciation of invention are properly evaluated, the overwhelming factual evidence supports that the government’s contention that the Borchelt group members are the true inventors of claims 7, 8, 10 and 11 the ’094 patent by first conceiving an Alzheimer’s disease mouse model that expresses the Swedish mutation (APPswe) and a presenilin mutation (specifically, A246E), so as to produce accelerated beta-amyloid (Aβ) deposition in the mouse brain. The evidence further shows that the group was diligent in reducing their invention to practice as well, as documented in the 1997 Neuron Article1. In fact, the Borchelt group reached all of the early research benchmarks of research before the Hardy/Duff group. 1 Throughout this brief, “the 1997 Neuron Article” will refer to the article found at Ex. 16, Borchelt, et al., “Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins,” Neuron 19(4):939–40 (1997). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 6 of 42 2 While USF alleges that it also first conceived its invention in 1995, there is no corroborating evidence to legally establish this as a conception. In contrast, by 1995, the Borchelt group, as corroborated by laboratory notebooks, had created founder lines for (1) mice expressing the APPswe mutation, and (2) mice expressing one of three presenilin mutations (including the A246E mutation used by the Borchelt group, and the M146L mutation ultimately used by the Hardy/Duff group). The Borchelt group’s grant documents, prepared in late 1995, corroborate the Borchelt group’s intentions to provide improved and enhanced mouse models to study the pathology of Alzheimer’s disease. USF’s motion principally argues that Dr. Borchelt somehow did not “appreciate” his invention based primarily upon (1) his group’s interim work leading to the 1996 Neuron Article2 and (2) his statement that he did not intend to make models of Alzheimer’s disease itself. Solely on these bases, USF concludes that the Borchelt group is not entitled to a 1995 or 1996 conception date. Those arguments are specious. The work leading to the 1996 Neuron Article was conducted while the initial double-transgenic mice were aged for 12 months—in order to evaluate beta-amyloid deposits in their brains. This related research studied how levels of specific peptides closely associated with deposition were elevated in younger double-transgenic mice of the same type. Thus, this 1996 research reflects a pursuit of, rather than a diversion from, the goals of the Borchelt group in developing double-transgenic mice that produced accelerated Aβ deposition. 2 Throughout this brief, “the 1996 Neuron Article” will refer to the article found at Ex. 15, Borchelt, et al., “Familial Alzheimer’s Disease-Linked Presenilin Variants Elevate Aβ1-42/1-40 Ratio In Vitro and In Vivo,” Neuron 17:1005–13 (1996). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 7 of 42 3 Similarly, USF distorts Dr. Borchelt’s statement that he was not seeking to make models of Alzheimer’s disease itself. As his later testimony and corroborating documentation make clear, Dr. Borchelt was intending to make mice that modeled pathological features of the human disease, just as the claims of the ’094 patent are themselves directed. II. COUNTERSTATEMENT OF FACTS A. GOVERNMENT’S RESPONSES TO USF’S STATEMENT OF MATERIAL FACTS USF’s Statement of Material Facts Not in Dispute (Nos. 1–22) contain many factual assertions that are disputed, immaterial, and unfounded. In accordance with Rule 56(c) of the Rules of the Court of Federal Claims (RCFC), each of these asserted facts are addressed individually below: 1. [Drs.] Hardy and Duff conceived of the invention of the Claims of the ‘094 Patent (Ex. 10) in 1995. KD (Ex. 1) 97: 9–13. Response: Denied. USF has failed to identify corroborating evidence supporting a Duff/Hardy conception in 1995. Dr. Duff, USF’s Rule 30(b)(6) witness on such topics could not identify any documents prior to September 1996 that in her view evidenced the conception. Ex. 1 at 97:9– 98:18. 2. The Hardy/Duff conception of the invention is reflected in the NIH Grant Application (Ex. 18) submitted by USF naming Hardy as principal investigator dated September 29, 1995. (The grant application, Section IV, provided “We also aim to cross our PS-1 mice with normal and mutant APP mice to study the effect of PS gene manipulation on human APP.” Section IV). SS (Ex. 3) 30:13–34:20. Response: Denied. As described herein, this vague statement of general research aims is legally insufficient to corroborate the Hardy/Duff conception date, particularly in view of USF’s position that the NIG Grant No. AG014633 did not fund any inventions encompassed by the Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 8 of 42 4 ’094 patent. See Dkt. No. 118 at 2–3 (“All of the work that was done, from conception to first actual reduction to practice, on the subject matter claimed in the ’094 Patent (Ex. 10) was done at USF without any funding from the United States!”). The referenced statement in Project IV of the grant application appears at Ex. 18 at 191 (HHS 00527). The statement does not specify what APP mutation was intended for use in Project IV, but Dr. Duff, the Project Leader for that project, in addressing a similar passage, Ex. 18 at 196–97 (HHS 00529–30), testified that this work was “speculation” and never done, and in fact related to other APP-mutant mice, including the Athena (PDAP) mouse. Ex. 1 at 179:15–183:12. The description of Project IV does not mention an APPswe mutant mouse. Ex. 18 at 184–98 (HHS 00520–34). 3. The Hardy/Duff invention claimed in the ‘094 Patent (Ex. 10) was subsequently published in a paper by Holcomb et al (Ex. 14) that referenced the NIH grant AG014633 (Ex. 18) that was submitted by USF naming Hardy as principal investigator in 1995. SS (Ex. 3) 52:8– 23. Response: Admitted. 4. Duff and Hardy disclosed the invention of the ‘094 Patent (Ex. 10) as an invention in September, 1996 on an invention disclosure form for the University of South Florida. KD (Ex. 1) 55:21–57:13. Response: Denied. Exhibit 19 is the referenced invention disclosure form, but it does not disclose the claimed inventions of the ’094 patent. Rather, at most, it vaguely describes the disclosed invention(s) as, in part, involving crossing mice with a presenilin transgene “with other transgenic animals (with APP or other Alzheimer-related transgenes) may allow the initiation of pathology though a multiplicative effect, even though each parental strain did not develop pathology on its own.” Ex. 19 at USF 02057. Dr. Duff admitted that this passage discusses the Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 9 of 42 5 APP mutations in general and described the invention more “broadly” than the ’094 patent. Ex. 1 at 64:22–65:24. 5. The work at USF including breeding and cross-breeding the transgenic mice to reduce the invention of the ‘094 Patent (Ex. 10) to practice began no later than about the beginning of August of 1996. MG (Ex. 4), 71:14–25. Response: Admitted in part. The government admits only that Dr. Gordon testified, in the cited portion, that “the first ones were born on the 21st of August, and, so, that means they were mated together on the first of August because that’s how long it takes them.” Ex. 4 at 71:23–25. 6. Work on actually reducing the invention of the ‘094 Patent (Ex. 10) to practice by cross-breeding mice expressing the APPswe mutation with mice expressing a presenilin mutation and assessing and characterizing those mice began in August 1996 with “near daily diligence” at USF leading to an actual reduction to practice in April of 1997. Ex. 8, Declaration of Marcia Gordon, ¶¶ 6–7. Response: Admitted in part. The government admits only that the Gordon Declaration3, in the cited portions, states that certain breeding and testing was conducted “with near-daily diligence at USF in the period December, 1996 – October, 1997.” Ex. 8 at ¶ 7. 7. Duff characterized an actual reduction to practice of the invention claimed in the ‘094 Patent (Ex. 10) in a statement dated April 25, 1997 sent to USF’s Office of Patents and Licensing. KD (Ex. 1) 126: 3–135:5. Response: Admitted in part. Dr. Duff does appear to characterize, in the cited document, research results that, in her view, are indicative of a patentable invention in her April 25, 1997 3 Dr. Gordon’s Declaration (Ex. 8) was signed in June 2017, but provided to government counsel for the first time by USF counsel during her deposition in August 2018. See Ex. 4 at 68:5–69:12. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 10 of 42 6 facsimile to USF’s Office of Patents and Licensing. Ex. 1 126:3–135:5. The government denies any other allegation in paragraph 7, including any legal conclusions regarding a “reduction to practice.” 8. William Coppola, who was at USF’s Patent and Licensing office in 1997 confirmed receipt of the facsimile reflecting Karen Duff’s report on an actual reduction to practice as the type of thing he would have received from her in the course of his work. Ex. 7, Declaration of Coppola, ¶ 6. Response: Admitted in part. The government admits only that the statement in paragraph 8 is supported by the cited Coppola Declaration. The government otherwise lacks sufficient information to admit or deny the allegations of paragraph 8. 9. Stephen Snyder, grant program administrator at NIH and the witness identified by the Government as its 30(b)(6) witness on matters pertaining to NIH funding specifically selected David Borchelt to be one of the members of the committee that would review the application for funding submitted by Hardy. SS (Ex. 3) 39:14–44:6 (“Dave Borchelt, with his background, was really an ideal candidate as a reviewer”). Response: Admitted in part. The government admits that Dr. Stephen Snyder is a former grant administrator with the NIH and testified as a Rule 30(b)(6) witness as to grant funding at issue. The government further admits that Dr. Snyder testified that Dr. Borchelt was a reviewer of the grant, though it is unclear what portions of the grant he reviewed and when. Moreover, Dr. Borchelt was never questioned as his deposition regarding his role as a reviewer on the grant in question. Ex. 2. The only written record of Dr. Borchelt’s participation authenticated by Dr. Snyder was dated January 30, 1996. Ex. 3 at 82:13–84:7. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 11 of 42 7 10. All members of the review team that assessed the Hardy NIH grant application approved as grant AG014633 (Ex. 18) were required to specifically note any conflicts of interest they might have in reviewing the application for grant, and if they had no conflicts, they were required to expressly so state. SS (Ex. 3)41: 20–42:13. Response: Admitted in part. The government admits only that Dr. Snyder testified, in the cited portion, that “part of the review process involved their – I don’t know that they took an oath, but specifically acknowledge any conflicts of interest,” but added that “in truth, what you really want is someone who is willing to take on that responsibility [as a reviewer] and be objective in their criticisms.” Ex. 3 at 42:6–16. 11. David Borchelt at no time indicated he had a conflict of interest in reviewing the Hardy/Duff grant application that pertained to making transgenic mice expressing presenilin mutations and APP mutations and exhibiting accelerated Alzheimer’s Disease pathology. SS (Ex. 3), 44:5–21. Response: Denied. The government lacks sufficient information to admit or deny these allegations. Dr. Snyder testified at deposition, in the cited portion, that he did not recall or have any knowledge on any conflicts of interest held by Dr. Borchelt. Ex. 3 at 44:5–21. Dr. Borchelt, for his part, was never questioned about these allegations at his deposition. See generally Ex. 2. 12. Borchelt testified that the doubly transgenic mice of Borchelt’s 1996 Neuron paper (Ex. 15) did not clearly show an increase in expression of Aß-42 over the singly transgenic mice, a feature of the invention of the ‘094 invention. DB (Ex. 2) 26:6–10. Response: Denied. USF has misrepresented Dr. Borchelt’s testimony and the results of the 1996 Neuron Article. As Dr. Borchelt testified, the research reflected in the 1996 Neuron Article studied the changes in ratio of Aβ-42 to Aβ-40 (the most prominent form of Aβ) in order to make Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 12 of 42 8 the most accurate measurements because “across multiple samples of animals, to get an accurate number of how much absolute peptide there is is challenging,” particularly with mice that young. Ex. 2 at 26:6–27:10. The 1996 Neuron Article, in turn, found that the double-transgenic mice had elevated Aβ1-42/1-40 ratios. Ex. 15 at 2–3. 13. The study and results reflected in the Borchelt et al 1996 Neuron paper (Ex. 15) were based on mice sacrificed at a young age, before any amyloid deposits in the brain could form. DB (Ex. 2), 26:12–17. Response: Admitted. 14. Borchelt’s group made a decision in 1996 not to wait to conduct experiments on doubly transgenic mice to see if they would form amyloid plaques or deposits earlier than the parental lines because it would take too much time to age the mice, and Borchelt wanted to publish something new before then. DB (Ex. 2), 30:17–31:19. Response: Admitted in part. The government admits only that, in the cited testimony, Dr. Borchelt testified that in his business “you publish or perish” and his group “made a tactical decision that we could not wait – we could not wait to see whether our doubly transgenic mice would get amyloid plaques.” Ex. 2 at 30:17–31:19. Thus, the experiments related to the 1997 Neuron Article had to wait “another six to nine months before” the mice were old enough. So, other experiments were conducted in the interim (related to the 1996 Neuron Article), but not to supplant the research on deposition ultimately published in the 1997 Neuron Article. 15. The Borchelt 1996 Neuron publication (Ex. 15) does not reflect any information on amyloid deposits or accelerated Alzheimer’s Disease pathology in the brain of mice expressing both APPswe and presenilin mutations. DB (Ex. 2) 24: 22–31:19. Response: Admitted in part. The 1996 Neuron Article does not provide data on amyloid Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 13 of 42 9 deposits. This is because the double-transgenic mice studied at this early time period were too young to produce deposits or similar pathology. Ex. 2 at 26:12–16. It does provide data on elevated levels of Aβ1-42(43), which as the Article itself points out, play “a role in the pathogenesis of AD.” Ex. 15 at 6. 16. Another publication by Borchelt et al in 1996, Ex. 17, Genetic Analysis, was prepared and submitted before the Borchelt group had aged their mice and does not disclose if the doubly transgenic mice expressing the APPswe mutation and a presenilin mutation exhibited any accelerated Alzheimer’s Disease pathologies including amyloid deposits, reactive gliosis, loss of cognitive function, neurofibrillary tangles or significant neuronal loss. DB (Ex. 2) 35:3– 38:19. Response: Admitted in part. The government admits only that the 1996 Genetic Analysis paper was submitted before the 12-month-old mice were sacrificed in 1997, and that the article does not disclose research on Alzheimer’s disease pathologies as it relates to “an expression plasmid for use in transgenic mice,” specifically mice expressing APP genes. Ex. 17 at 1 (Abstract); see also Ex. 2 at 32:7–33:22. 17. Mice raised by Borchelt et al with presenilin mutations but not a APP mutation in 1996 exhibited no Alzheimer’s Disease pathology. (“I could find nothing wrong with them, no proteolysis, no nothing.”) DB (Ex. 2) 48:9–49:16. Response: Admitted in part. The government admits only that Dr. Borchelt testified that, in the context of his work for the 1996 Neuron Article, his research looked at “presenilin mice that had all the mutations, wild-type and – multiple lines of mutant presenilin, multiple lines of wild-type that aged out for 20, 24 months that had nothing – I could find nothing wrong with them, no 14 Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 14 of 42 10 proteolysis, no nothing.” Ex. 2 at 49:9–16. Dr. Borchelt could not recall where this finding was published. Ex. 2 at 49:14–16. 18. Borchelt et al continued their research on mice expressing a presenilin mutation and the APPswe mutation during 1997, which culminated in the publication of the third article on this study, Neuron October 1997, (Ex. 16) in which the doubly transgenic mice were aged sufficiently to observe amyloid deposits in the brain. DB (Ex. 2) 52:11–16. Response: Admitted. 19. In the October 1997 Neuron Article (Ex. 16), the doubly transgenic mice were shown for the first time to have higher severity of amyloid deposits in the brain than singly transgenic presenilin mice. DB (Ex. 2) 55:3–56:6. Response: Denied. The first publications of these results was the 1997 Neuron Article, but the Borchelt work demonstrating these results, by definition, occurred before the first publication. See, e.g., Dkt. No. 106 at 9–10. 20. Borchelt could not recall any presentation made by any member of his group on the results of the study on the amyloid deposits of the doubly transgenic mice before its publication in Neuron, October 1997 (Ex. 16). DB (Ex.2) 56:12–59:2. Response: Admitted in part. Dr. Borchelt did not recall any presentations, but indicated that such presentations “probably” happened, by Dr. Sisodia or by Dr. Price, who were both “out on the road all the time.” Ex. 2 at 56:7–21. Furthermore, the government’s invalidity contentions, and the cited Sisodia Declaration (Dkt. No. 58-6) both indicate that Dr. Sisodia indeed made such presentations. Dkt. No. 58-6 at ¶¶ 19–20; Dkt. No 106 at 9 & n.13. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 15 of 42 11 21. No patent application directed to the doubly transgenic mice reported on in the Neuron publications of 1996 and 1997 (Exs. 15 and 16 herein) was ever filed. DB (Ex. 2) 14:7– 16. Response: Admitted. 22. David Borchelt testified that he had a conflict of interest in cooperating with USF as a witness in this litigation, in that he stood to monetarily benefit if the ‘094 Patent (Ex. 10) was invalidated. DB (Ex. 2) 5:1–6:22. Response: Denied. This paragraph mischaracterizes Dr. Borchelt’s testimony. He was asked why he was “reluctant” to provide documentation to USF counsel, when they reached out to him in December 2017. He indicated he had a “conflict of interest” and the cited testimony shows that Dr. Borchelt was transparent about these alleged conflicts of interest, testifying that he would potentially benefit regardless of who won (or in other words, if USF won or lost). Ex. 2 at 5:1–6:22. Accordingly, Dr. Borchelt indicated that he “did not want to be on either side.” Ex. 2 at 7:15–16. B. GOVERNMENT’S ASSERTED MATERIAL FACTS Pursuant to RCFC 56(c), the government hereby asserts its statements of undisputed material facts (with supporting citation) in support of its opposition. 1. Borchelt Group Research 1. The government has asserted a 35 U.S.C. §102(g) based on research activities of a research group headed by Dr. David Borchelt, then working as a researcher at Johns Hopkins University School of Medicine. See, e.g., Dkt. No. 106. This research was ultimately published in 1996 in the 1996 Neuron Article and in 1997 in the 1997 Neuron Article. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 16 of 42 12 2. A third paper cited by USF, the 1996 Genetic Analysis Article4 (Ex. 17), describes the vectors that were used to make the founder lines (expressing particular transgenes), which were bred to create Dr. Borchelt’s double-transgenic mice. Ex. 17 at 3 (use of plasmid for APPswe), 4 (use of plasmid for presenilin transgenes); Ex. 2 at 66:8–67:12 (discussing Ex. 17 (Ex. 4 to Borchelt deposition)). The 1996 Genetic Analysis Article was received for publication on May 20, 1996. Ex. 17 at 1 (listing below author list). 3. The Borchelt group included Dr. Sangram Sisodia, whose laboratory at Johns Hopkins University was used for much of the research. See Dkt. No. 58-6 at ¶ 19. 4. Other members of the Borchelt group include individuals listed as authors on Dr. Borchelt’s 1996 Neuron Article and 1997 Neuron Article, which documents the group’s research. See Dkt. No. 58-6 at ¶¶ 19–23; Ex. 15 at 1; Ex. 16 at 1. 5. Of these researchers listed as authors, Dr. Steven Younkin was the only individual that was common to both the Borchelt group and the Duff/Hardy group. See Ex. 14 at 1; Ex. 15 at 1 (both listing Dr. Younkin as an author). 6. The Borchelt group conceived of claimed inventions of the ’094 patent in 1995. Ex. 31 at 2 (¶ 7). 7. The impetus for the Borchelt group’s initial conception and later research was that Dr. Borchelt and others reviewed a paper from Dr. Younkin’s laboratory in 1994 that found that APP processing was associated with development of the disease, which in turn piqued the Borchelt group’s interest in researching presenilins. Ex. 2 at 17:11–18:19; Ex. 31 at 2 (¶ 8). The article reviewed was Suzuki et al., “An Increased Percentage of Long Amyloid Beta Protein 4 Borchelt, et al., “A Vector for Expressing Foreign Genes in the Brains and Hearts of Transgenic Mice,” Genetic Analysis: Biomolecular Engineering 13:159–63 (1996). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 17 of 42 13 Secreted By Familial Amyloid Beta Protein Precursor (Beta APP717) Mutants,” Science, 27;264(5163):1336–40 (May 1994). Ex. 31 at 2 (¶ 8). 8. By March 1995, the Borchelt group made founder (parental) lines that expressed the Swedish mutation (APPswe). Ex. 31 at 2 (¶ 9) (discussing Ex. 21 at BOR_0608–10). 9. The Borchelt group in the fall of 1995 began making the founder lines (parental mice) with three different presenilin transgenes, including M146L and A246E, which were crossed to make the double-transgenic mice. Ex. 2 at 98:10–99:7. Some of these lines are specifically documented in Dr. Borchelt’s laboratory notebooks. See Ex. 2 at 99:8–101:13 (discussing Ex. 21, notebook materials marked as Ex. 5 in Borchelt deposition); Ex. 31 at 2–3 (¶ 10). 10. The Borchelt group’s 1995 work is also documented by grants that funded his work. See Ex. 2 at 16:8–13. The relevant grant, Grant No. 1P01AG014248, has a March 1997 budget award date, but the listed budget start date is October 1996. Ex. 22 at BOR_0671 (public NIH Reporter records). The normal interval between grant submission and projected start date is about 9 months. This interval is set by the NIH to allow time for peer review of the proposal. Accordingly, the application for this grant was submitted in early 1996, but not actually awarded until early 1997. Thus, the preparation of this application for this grant, by Dr. Borchelt and others, likely occurred in late 1995. Ex. 31 at 3 (¶¶ 11–12). 11. Grant No. 1P01AG014248 is referenced in the 1997 Neuron Article as supporting research published in that paper. See Ex. 16 at 11; Ex. 31 at 3 (¶ 13). 12. The Abstract of Grant No. 1P01AG014248 states that one project goal involved the production of transgenic PS mutation mouse models—“for the first time, PS mutation linked trangenic [sic] models of FAD in which it will be possible to examine the mechanisms of disease Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 18 of 42 14 and to test potential therapies.” Ex. 22 at BOR_0672 (publicly available NIH Reporter materials). The relevant project description relating to transgenic mice highlights the Borchelt group’s specific plans to make double-transgenic mice: Several lines of evidence strongly encourage us in this effort: the expression plasmid vector drives the expression of APP and PS1 in a relatively copy-dependent manner; and using these approaches, we have already generated founders harboring PS1-wt and PS1-A246E cDNA transgenes and PS1 nucleic acid probes, and antibodies have demonstrated that our transgene construct expresses wt and mutant PS1 at relatively high levels (about 5 fold over endogenous). We anticipate that mice expressing high levels of mutant PS1/PS2 will develop behavioral/brain abnormalities that share features with FAD. Moreover, through breeding paradigms, lines of APP transgenic or null mice can be used to explore the interactions of PS1/PS2 and APP in the pathogenesis of disease. We are confident that these efforts will lead to development of transgenic models of FAD, the study of which will clarify the mechanisms of disease. Ex. 22 at BOR_0670 (emphases added); see also Ex. 31 at 3–4 (¶ 14). 13. Ultimately, the founder lines (specifically those expressing the APPswe and A246E transgenes) were crossed so as to produce mice that could be used in the research leading to the 1996 Neuron Article and the 1997 Neuron Article. Ex. 2 at 140:12–141:20. While founder lines had been made with two other presenilin transgenes (including M146L), the A146E mouse line was chosen because it was the best founder line and also the first made by the Borchelt group. Ex. 2 at 101:20–103:16. Dr. Borchelt explained that “The people who were involved in the 146L [founder mice] in the exon 9 deletion [founder] mice did not appreciate how competitive we were, how much competition there was, and how important it was to get this going as quickly as possible. So I worked weekends and nights and that person did not.” Ex. 2 at 103:11–16. 14. The double transgenic mice that had to be aged the longest, 12 months, were bred first for that reason. These were mice that were to be studied for amyloid deposits, the results of which were published in the 1997 Neuron Article. Ex. 2 at 58:7–21, 141:4–10. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 19 of 42 15 15. These 12-month mice were first born no later than April 1996. Dr. Borchelt’s notebook materials, for example, identify one particular mouse (based on its cage card, Ex. 23 at BOR_0300-01) born on April 13, 1996 with both the APPswe mutation and the A246E mutation. Ex. 2 at 125:7–126:12. These were among the first mice that were bred for the eventual 1997 Neuron Article. Ex. 2 at 126:9–12, 140:16–18. 16. The 1997 Neuron Article also includes double-transgenic mice that were sacrificed as young as nine months, Ex. 16 at 7 (chart), but those mice were bred later than the 12-months, so as to shorten the overall length of the experiments. Ex. 2 at 58:7–21. 17. Another group of double-transgenic mice (also expressing the APPswe and A246E transgenes) were bred for the research leading to the 1996 Neuron Article, likely first born in June 1996. Ex. 2 at 141:7–20. 18. From this point forward, research on the mice for both Articles moved forward concurrently. See infra Parts II.B.2 through 4. 2. Further Research Leading to the 1997 Neuron Article 19. By April 1997, the 12-month aged mice—bred first for the 1997 Neuron Article—were being sacrificed and tested. For example, the mouse born on April 13, 1996, was sacrificed on April 9, 1997, so that its brain could be studied for Alzheimer’s pathology (i.e., beta amyloid deposition). Ex. 2 at 126:13–127:8 (discussing cage card, Ex. 23 at BOR_0300– 01). 20. Written records additionally show that this mouse’s brain was “cut” or prepared for testing on April 15, 1997, and then the sample was stained on April 18, 1997. Ex. 2 at 128:21–132:15 (discussing Ex. 23 at BOR_0293). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 20 of 42 16 21. A worksheet for additional (staining) testing for the same double-transgenic mouse was initiated on May 7, 1997 and delivered on June 25, 1997. Ex. 2 at 132:17–135:14 (discussing Ex. 23 at BOR_0295). 22. Data collected from mice like these showed that they exhibited accelerated beta- amyloid deposition at 12 months of age. Ex. 2 at 135:19–39:25. 23. Data from the Borchelt double-transgenic mouse were ultimately received for publication on June 19, 1997. Ex. 2 at 145:18–146:6; Ex. 16 at 15. The 1997 Neuron Article was published in October 1997. Ex. 16 at 2. 24. The 1997 Neuron Article reports, inter alia, that co-expression of APPswe and the A246E presenilin mutation “dramatically” accelerates the extent and frequency of beta-amyloid deposits. Ex. 16 at 6–7. As shown in Table 1 of the Article, Aβ deposits appeared in the double- transgenic mice at 9 months of age and greatly increased in frequency up to 12 months of age, whereas mice expressing APPswe alone did not appear at all until 18 months. Ex. 16 at 6–7; Ex. 2 at 52:22–56:9. 25. Dr. Sisodia presented results of this paper in a small window of time prior to publication of the 1997 Neuron Article. See Dkt. No. 106 at 9 & n.13; Ex. 2 at 58:3–21. 3. Further Research Leading to the 1996 Neuron Article 26. For the research published in the 1996 Neuron Article, those mice were sacrificed at 2–4 months of age (before deposits could form) but were evaluated for whether they produced excess Aβ-42 (as measured by a ratio to nonpathogenic Aβ-40). The resulting mice did in fact produce excess extracellular Aβ-42 (a species of beta-amyloid protein closely associated with Alzheimer’s) as compared to mice expressing only APPswe. Dkt. No. 58-6 at ¶ 19; Ex. 15 at 6 (noting “several lines of evidence . . . that Aβ1-42(43) plays a role in the pathogenesis of AD” Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 21 of 42 17 and providing Figure 5 that plots ratios); see also Ex. 2 at 26:12–30:8 (describing ratio measurements). 27. To further examine the effects of the presenilin mutation(s) on the ratio of Aβ, the 1996 Neuron Article also provided research regarding the amount of Aβ1-42(43) produced in cell lines expressing one of three mutant presenilin transgenes (M146L, A246E, and ∆E9), the same transgenes used in the Borchelt group’s founder lines. Ex. 15 at 2–3; Ex. 2 at 94:20–97:10. 28. In June and July of 1996 (or possibly earlier), Dr. Sisodia began presenting these results and discussing the team’s work at academic conferences. Dkt. No. 58-6 at ¶ 20. 29. The 1996 Neuron Article was submitted in August 1996 and ultimately published in November 1996. Dkt. No. 58-6 at ¶ 21. 30. The 1996 Neuron Article explains its results as providing “compelling support for the view that mutant presenilin acquires property(ies) that influence APP processing in a manner that results in elevated extracellular concentrations of Aβ1-42(43), a highly amyloidogenic peptide that is selectively deposited in the brains of individuals with AD and Down’s Syndrome.” Ex. 15 at 3. Thus, the Article’s research on elevated Aβ1-42(43) levels in the brains of Borchelt double-transgenic mice is closely tied to the examination of beta-amyloid deposition with the same mice documented in the 1997 Neuron Article. 31. Dr. Borchelt submitted an invention disclosure related to his research on double- transgenic mice, but that Johns Hopkins University, his employer, declined to pursue a patent because it “felt that such patents were not profitable and difficult to defend and they generally had a policy of not thinking it was worth the time and effort.” Ex. 2 at 15:21–16:2. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 22 of 42 18 4. Hardy/Duff Research 32. In opposition to the government’s claims of prior invention, USF contends that the Hardy/Duff team (led by the named inventors of the ’094 patent) conceived of the invention(s) of the ’094 patent in 1995. Dkt. No. 117 at 4 (¶ 2). 33. This conception date was first asserted by USF during the July 31, 2018 deposition of Dr. Duff, USF’s Rule 30(b)(6) witness on such topics. See Ex. 1 at 1 (cover page). Dr. Duff’s deposition occurred after Dr. Borchelt’s deposition. See Ex. 2 at 1 (cover page). 34. Prior to Dr. Duff’s deposition, USF asserted a conception date of “no later than July 4, 1996.” Ex. 1 at 99:6–101:25. 35. Dr. Duff, the Rule 30(b)(6) witness for USF, however, testified that USF had no corroborating records of this conception. Ex. 1 at 97:23–98:18. She stated that there was merely a “discussion” of the invention at that time. Ex. 1 at 101:24–102:4; see also Ex. 1 at 97:9–98:22. 36. In its motion, USF alleges one written statement corroborating its 1995 conception in the description of Project IV in the AG14633 grant: “We also aim to cross our PS- 1 mice with normal and mutant APP mice to study the effect of PS gene manipulation on human APP.” Dkt. No. 117 at 2 (¶ 4) (citations omitted). Dr. Duff, the Project Leader for Project 4, addressing a similar passage, Dkt. No. 117 at 196–97 (HHS 00529–30), testified that this work was “speculation” and never done, and in fact related to other APP-mutant mice, including the Athena (PDAP) mouse. Ex. 1 at 179:15–183:12. The description of Project IV does not mention an APPswe mutant mouse. Ex. 18 at 184–98 (HHS 00520–34). 37. Highlighting the weakness of USF’s vague claims to a conception in 1995, Dr. Morgan testified that “we wrote that grant before the idea of this [double-transgenic mice] were developed, but by the time we got the grant, this idea was well in place and underway.” Ex. 5 at 37:15–17. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 23 of 42 19 38. Also undermining USF’s vague claims to a 1995 conception, the USF Invention Disclosure Form submitted by Dr. Duff in a September 13, 1996 facsimile broadly described the invention as “Breeding presenilin transgenic mice to modulate amyloid deposition.” Ex. 19 at USF 002050. There is no discussion of creating a double-transgenic mouse with the APPswe mutation. 39. The Hardy/Duff group began breeding the M146L founder lines that were used to make the double-transgenic mice of the ’094 patent in “early summer of 1996.” Ex. 1 at 91:12– 22. 40. The Hardy/Duff group obtained a APPswe line from Karen Hsiao, who provided it to Dr. Hardy. Ex. 1 at 45:6–11, 107:17–21; Ex. 4 at 47:6–12, 73:8–13. 41. Dr. Gordon, Dr. Duff and other USF personnel then bred the first litter of double- transgenic mice disclosed in the ’094 patent beginning in early August 1996, with the first mice born on August 21, 1996. Ex. 4 at 71:15–25, 73:18; see also Ex. 1 at 137:2–138:24. 42. The submitted Declaration from Dr. Gordon describes only her activities in breeding, rearing and testing double-transgenic mice (and other littermates) from December 1996 to October 1997. Ex. 8 at 4 (¶ 7). 43. By USF’s admission (Dkt. No. 117 at 5 (¶ 7), 11), the first documentation of an actual reduction to practice by the Hardy/Duff group is found in a facsimile to William Coppola, dated April 25, 1997. Ex. 7 at 6–9. The facsimile describes how double-transgenic mice (along with mice with only one transgene) were sacrificed at 5.5 months of age, and then their brains were analyzed. Ex. 7 at 7. 44. According to the Coppola facsimile, the double-transgenic mice showed “Alzheimer’s type pathology at 5.5 months,” specifically accelerated beta-amyloid deposition, as Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 24 of 42 20 compared to mice expressing only the APPswe transgene. Ex. 7 at 7. The document specifically points to a “Figure 2,” which identifies beta-amyloid deposits in the brain of double-transgenic mouse. 45. USF’s research on double-transgenic mice was received by the Nature Medicine journal on July 24, 1996. Ex. 14 at 5. It was published in January 1998 (the 1998 Nature Paper5), and describes the invention(s) of the ’094 patent, namely double-transgenic mice that exhibit accelerated pathology of Alzheimer’s disease. Ex. 14; Dkt. No. 118 at 5, 11 (USF admitting same). III. ARGUMENT A. LEGAL STANDARDS 1. Summary Judgment Standard Summary judgment is appropriate only if USF can prove that the evidence of record (including “the pleadings, depositions, answers to the interrogatories, and admissions on file, together with the affidavits, if any”) “show that there is no genuine issue as to any material fact and that the moving party is entitled to a judgment as a matter of law.” RCFC 56(c); Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 249–50 (1986). A “genuine” dispute exists when the issue “may be reasonably resolved in favor of either party.” Id. at 250. A fact is “material” when “it might affect the outcome of the suit under the governing law.” Id. at 248. As the moving party, USF has the burden of establishing that no genuine issue of material fact exists. See Celotex Corp. v. Catrett, 477 U.S. 317, 322–23 (1986). Therefore, the Court must draw all factual inferences “in the light most favorable to the party opposing the motion.” 5 Holcomb et al., “Accelerated Alzheimer-Type Phenotype in Transgenic Mice Carrying Both Mutant Amyloid Precursor Protein and Presenilin 1 Transgenes,” Nature Medicine 4 97–100 (1998). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 25 of 42 21 Matsushita Elec. Indus. Co. v. Zenith Radio Corp., 475 U.S. 574, 587–88 (1986) (quoting United States v. Diebold, Inc., 369 U.S. 654, 655 (1962)). 2. Defenses under Pre-AIA 35 U.S.C. § 102(g) With passage of the American Invents Act (AIA) in 2012, the U.S. patent system switched from a “first-to-invent” system to a “first inventor-to-file” system for patent applications filed on or after March 16, 2013. Thus, patents filed prior to 2013, including the ’094 patent, can be invalidated based on a prior inventor, as anticipated under the pre-AIA version of 35 U.S.C. § 102(g) or as obvious under 35 U.S.C. § 103. Pre-AIA Section 102(g) provides in relevant part that: A person is entitled to a patent unless -- (g) before the applicant's invention thereof the invention was made . . . by another who had not abandoned, suppressed, or concealed it. In determining priority of invention there shall be considered not only the respective dates of conception and reduction to practice of the invention, but also the reasonable diligence of one who was first to conceive and last to reduce to practice, from a time prior to conception by the other. Thus, one can prove a prior invention by establishing either “(1) it reduced its invention to practice first . . . or (2) it was the first party to conceive of the invention and then exercised reasonable diligence in reducing that invention to practice.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1332 (Fed. Cir. 2001). As described herein, the government’s assertions under 35 U.S.C. § 102(g) principally focus on the second prong, alleging a prior conception of the double-transgenic mice claimed in the ’094 patent by the Borchelt group in 1995 followed by diligence leading to an actual reduction to practice in 1997. B. THE GOVERNMENT’S CONTENTIONS Specifically, the government’s section 102(g) defense centers around a prior invention by Dr. David Borchelt and his research team, which worked primarily in Dr. Sangram S. Sisodia’s laboratory at the Johns Hopkins University School of Medicine. Dkt. No. 106 at 8 (citing Dkt. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 26 of 42 22 No. 58-6 at ¶ 19); Ex. 20 at 5–9. Specifically, the government alleges that Dr. Borchelt’s team (the Borchelt group) conceived of its double-transgenic mice in 19956 (when it developed founder lines with each mutation), bred the first double-transgenic mice in 1996, with the first mice born in early April 1996. These mice were eventually sacrificed, beginning in April 1997, when their brains were studied and ultimately found to have accelerated deposition of beta- amyloid protein (Aβ), as compared to single-transgenic mice (including parental mice). Thus, the government alleges a reduction to practice date no later than April 1997. USF’s motion asserts that “[t]he invalidity contentions of the United States (Docket 106) nowhere indicate precisely what ‘invention’ [Dr.] Borchelt and his team of investigators is argued to have invented in advance of the conception and reduction to practice of the invention of the ’094 patent (Ex. 10).” Dkt. No. 117 at 8–9 (emphasis added). USF further asserts that the government’s contentions “seem[s] to suggest the invention is simply mice that express a presenilin mutation and the APPswe [Swedish] mutation.” Dkt. No. 117 at 9. In that vein, USF notes that every claim of the ’094 patent “that the mice in question exhibit accelerated Alzheimer’s disease pathology.” Dkt. No. 117 at 10 (emphasis in original). Under the Court’s construction of that terminology, this includes, inter alia, accelerated deposits of Aβ, i.e. “forming at least one month earlier than the singly transgenic or non-transgenic parents.” Dkt. No. 101 at 14. 6 In the invalidity contentions, the government initially alleged a conception date no later than April 1996, in response to USF’s alleged conception no later than July 1996. Dkt. No. 106 at 13–16 & n.21. After Dr. Duff alleged a 1995 conception date in her deposition, Ex. 1 at 99:6– 101:25 (and after obtaining information from Dr. Borchelt’s deposition and his publicly available NIH grant documents), the government asserted a conception date no later than 1995 in its most recent interrogatory responses. Ex. 20 at 5–7 & n.2. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 27 of 42 23 These assertions are incorrect. The government’s invalidity contentions make clear that claims 7, 8, 10, and 11 are invalid as anticipated under 35 U.S.C. § 102(g), or alternatively, as obvious under 35 U.S.C. § 103. Dkt. No. 106 at 14–17; Dkt. No. 106-2 (claim chart detailing government’s section 102(g) contentions). The government further alleges that the remaining asserted claims (claims 1–3, 5, 9, and 12–14) are obvious in view of the Borchelt group’s work that constitutes section 102(g) prior art, particularly if Dr. Borchelt’s 1996 Neuron Article is deemed not to be prior art. See, e.g., Dkt. No. 106 at 24; Dkt. No. 106-4 (claim chart).7 Unlike claims 7, 8, 10, and 11, which do not specify a particular presenilin mutation, these claims are specific to the M146L mutation and thus the government does not allege that those claims are anticipated under section 102(g). Further, the government’s contentions make clear that each limitation of these claims has been addressed by the government. See Dkt. Nos. 106-2, 106-4. In particular, claim language related to accelerated Alzheimer’s disease pathology, was specifically addressed in the body of the government’s contentions and in the attached claim charts. See, e.g., Dkt. No 106 at 10 (noting that Borchelt group’s double transgenic mice were ultimately found to exhibit “deposition at least 9 months prior to any deposition by a single-mutant mouse”). 7 This claim chart specifically notes that The government also reserves the right to rely upon § 102(g) prior art to further supplement the evidence cited above, particularly such art showing that the Borchelt group determined that the APPswe/A246E mice exhibited ‘accelerated deposition,’ in accordance with the court’s construction.” Dkt. No. 106-4 at 1 n.2. The government has also stated in its interrogatory responses that “it is relying on Dr. David R. Borchelt and Dr. Sangram S. Sisodia [a Borchelt group member] for its positions regarding a prior invention under 35 U.S.C. § 102(g) by the Borchelt group. Ex. 20 at 25; see also Dkt. No. 106 at 8–11. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 28 of 42 24 C. PROVING PRIOR INVENTORSHIP REQUIRES CORROBORATING EVIDENCE. Prior inventorship (whether by an earlier conception or an earlier reduction to practice) requires the challenging party to offer corroborating evidence of its asserted dates of conception and reduction to practice. There are three primary elements of proof. First, an alleged conception must be corroborated by independent evidence when any party seeks to prove conception through oral inventor testimony. See In re Jolley, 308 F.3d 1317, 1321 (Fed. Cir. 2002) (citing Price v. Symsek, 988 F.2d 1187, 1190 (Fed. Cir. 1993)). “This requirement arose out of a concern that inventors testifying in patent infringement cases would be tempted to remember facts favorable to their case by the lure of protecting their patent or defeating another's patent.” Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1577–78 (Fed. Cir. 1996) (citing Eibel Process Co. v. Minn. & Ont. Paper Co., 261 U.S. 45, 60 (1923)). “Conception must be proved by corroborating evidence which shows that the inventor disclosed to others his ‘completed thought expressed in such clear terms as to enable those skilled in the art’ to make the invention.” Coleman v. Dines, 754 F.2d 353, 359 (Fed. Cir. 1985) (quoting Field v. Knowles, 183 F.2d 593, 600 (C.C.P.A. 1950)). However, “there is no final single formula that must be followed in proving corroboration.” Kridl v. McCormick, 105 F.3d 1446, 1450 (Fed. Cir. 1997) (quoting Berry v. Webb, 412 F.2d 261, 266 (C.C.P.A. 1969)). Second, the party alleging prior invention must also be able to show diligence “from a date just prior to the other party’s conception to . . . [the date of] reduction to practice [by the party first to conceive].” Monsanto Co. v. Mycogen Plant Sci., Inc., 261 F.3d 1356, 1369 (Fed. Cir. 2001). There is no rule requiring a specific type of activity in determining whether the applicant was reasonably diligent in proceeding toward an actual or constructive reduction to practice from the date of conception. See Brown v. Barbacid, 436 F.3d 1376, 1380 (Fed. Cir. 2006) (“Unlike the legal rigor of conception and reduction to practice, diligence and its Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 29 of 42 25 corroboration may be shown by a variety of activities . . . .”). It is also not necessary for a party alleging prior invention to drop all other work and concentrate solely on the particular invention involved. Rines v. Morgan, 250 F.2d 365, 369 (C.C.P.A. 1957). There need not be evidence of activity on every single day if a satisfactory explanation is evidenced. Monsanto, 261 F.3d at 1369 (citations omitted). One need not prove the alleged first inventor continuously exercised reasonable diligence throughout the critical period; it must show there was reasonably continuous diligence. See, e.g., Tyco Healthcare Grp. v. Ethicon Endo-Surgery, Inc., 774 F.3d 968, 975 (Fed. Cir. 2014). Third, any party alleging the earliest conception must show an actual reduction to practice. Kimberly-Clark Corp. v. Johnson & Johnson, 745 F.2d 1437, 1445 (Fed. Cir. 1984). This requires that the prior inventor “must have (1) constructed an embodiment or performed a process that met all claim limitations and (2) determined that the invention would work for its intended purpose.” Teva Pharm. Indus. Ltd. v. AstraZeneca Pharms. LP, 661 F.3d 1378, 1383 (Fed. Cir. 2011). Nonetheless, corroboration of actual reduction to practice does not require “every point of a reduction to practice be corroborated by evidence having a source totally independent of the inventor.” Cooper v. Goldfarb, 154 F.3d 1321, 1331 (Fed. Cir. 1998) (citations and internal quotations omitted). “Priority of invention and its constituent issues of conception and reduction to practice are questions of law predicated on subsidiary factual findings.” Singh v. Brake, 317 F.3d 1334, 1340 (Fed. Cir. 2003). The patentee has the burden of production in antedating a reference. Because a patent is presumed valid, however, the party challenging validity (here, the government) bears the burden of persuasion by clear and convincing evidence that the invention fails to meet the requirements of patentability. See Stamps.com Inc. v. Endicia, Inc., 437 Fed. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 30 of 42 26 Appx. 897, 907–08 (Fed. Cir. 2011) (citing Mahurkar, 79 F.3d at 1577–78); see also Apotex USA, Inc. v. Merck & Co., Inc., 254 F.3d 1031, 1037 (Fed. Cir. 2001). Nevertheless, if this burden is met, the burden of production shifts back to the patentee (USF) to produce evidence sufficient to create a genuine issue of material fact as to whether the prior inventor abandoned, suppressed, or concealed the invention. See Dow Chem. Co. v. Astro-Valcour, Inc., 267 F.3d 1334, 1339 (2001). D. USF WRONGLY ASSERTS THAT DR. BORCHELT DID NOT “APPRECIATE” HIS INVENTION AT THE TIME OF HIS GROUP’S ALLEGED CONCEPTION. Rather than properly evaluating the inventorship issue based on the alleged corroborating evidence that substantiates the conception and reduction to practice of the two groups’ work, USF instead argues that Dr. Borchelt and his team did not have “possession of the invention” as his group (in USF’s view) “did not appreciate the claimed inventive features . . . at the time of its alleged conception . . . .” Dkt. No. 117 at 12 (quoting Hitzeman v. Rutter, 243 F.3d 1345, 1358 (Fed. Cir. 2001) (citing Heard v. Burton, 333 F.2d 239, 242–44 (C.C.P.A. 1964)). Such an invalid “nunc pro tunc conception” is where a purported inventor fails to recognize an invention at the time of conception. Hitzeman, 243 F.3d at 1358. Under the law, there must be a contemporaneous recognition and appreciation of the invention for there to be conception. Silvestri v. Grant, 496 F.2d 593, 596 (C.C.P.A. 1974). Nevertheless, as Hitzeman points out, the government must only prove that “a reasonable expectation that the claimed result of the biological process would occur,” to establish an actual conception by the Borchelt group. Hitzeman, 243 F.3d at 1358. Accordingly, for a proper conception, an inventor does not need to know that the invention will work, Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994), nor appreciate the patentability of the invention, Dow Chem. Co., 267 F.3d at 1341. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 31 of 42 27 USF chiefly argues that the alleged 1995 conception by the Borchelt group fails to meet this legal standard because “he did not believe that the mice he had made were reasonable models of Alzheimer’s Disease.” Dkt. No. 117 at 12 (citing Ex. 2 at 16:21–17:10). But USF’s characterizations misrepresent what Dr. Borchelt clearly meant by that cited statement. Though accurately quoted, that he was not specifically seeking “models for Alzheimer’s disease,” Dr. Borchelt made clear that his group was seeking to make models that exhibited aspects of the pathology for Alzheimer’s disease, particularly accelerated Aβ deposition (or plaques), so as to better understand the mechanisms of the disease. Ex. 2 at 21:21–22:17, 24:8–18, 81:11–12. This is consistent with the description of the Borchelt group’s work in the relevant NIH grant supporting his work. Ex. 29; see also Ex. 2 at 16:8–13 (describing grant support). It states “through breeding paradigms, lines of APP transgenic or null mice can be used to explore the interactions of PS1/PS2 and APP in the pathogenesis of disease. We are confident that these efforts will lead to development of transgenic models of FAD, the study of which will clarify the mechanisms of disease.” Ex. 29 at BOR_0670 (emphases added).8 USF similarly argues that the Borchelt group also did not “appreciate” the invention(s) claimed in the ’094 patent in 1996 because it “made the conscious decision NOT to pursue research into that subject matter,” Dkt. No. 117 at 1, so that it could publish on matters unrelated 8 This position is also consistent with the claims of the ’094 patent and how they characterize the mouse models as demonstrating an Alzheimer’s disease pathology, not the disease itself. For example, claims 3–7 and 13–14 are directed to “[a] transgenic mouse with accelerated Alzheimer’s Disease related pathology.” Ex. 10 at 11–21 (14:52–15:21). Claims 1–2 are similarly directed to “[a] transgenic mouse model with enhanced Alzheimer’s Disease related amyloid accumulation,” Ex. 10 at 11 (14:17–53), and claims 7, 8 and 11 recite “a transgenic mouse with elevated levels of amyloidogenic Aβ(Aβ42(43)) as a pathology for Alzheimer’s disease,” Ex. 10 at 12 (15:12–32, 16:6–20). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 32 of 42 28 to Alzheimer’s disease pathology (including the 1996 Neuron Article), Dkt. No. 117 at 12–13.9 In USF’s view, “Borchelt’s very first statement [that his mice] exhibited Alzheimer’s Disease pathology” came in October 1997, when the 1997 Neuron Article was published. Dkt. No. 117 at 13. These arguments improperly distort Dr. Borchelt’s testimony and the close relationship between the research set forth in the 1996 Neuron Article and the 1997 Neuron Article. From 1995, it is clear that the Borchelt group was pursuing a double-transgenic mouse (APPswe x PS mutant) that, as a stated goal in the associated grant documents was “PS mutation linked trangenic [sic] models of FAD in which it will be possible to examine the mechanisms of disease and to test potential therapies.” Ex. 22 at BOR_0672. Other grant documents describe that the group already had mutant presenilin founders (A246E) and how “through breeding paradigms, lines of APP transgenic or null mice can be used to explore the interactions of PS1/PS2 and APP in the pathogenesis of disease.” Ex. 22 at BOR_0670. By April 1996, the Borchelt group was already breeding and rearing double transgenic mice. The first mice were purposely bred for the 1997 Neuron Article, knowing that they had to be aged 12 months so they could be studied for beta-amyloid deposits. Ex. 2 at 58:7–21, 141:4– 10. By June 1996, the same type of double-transgenic mice (APPswe x A246E) were being bred for use in the research on the eventual 1996 Neuron Article. Ex. 2 at 141:7–20. 9 USF’s motion also mentions another 1996 article that the Borchelt group published in the Genetic Analysis publication. Dkt. No. 117 at 7 (¶ 16), 13 (both citing Ex. 17). This article does not disclose research on Alzheimer’s disease pathologies because it relates to “an expression plasmid for use in transgenic mice,” specifically mice expressing APP genes. Ex. 17 at 1 (Abstract); see also Ex. 2 at 32:7–33:22. In other words, this article only described the “tools” to make a founder line expressing APP transgenic mice, but nonetheless relates to the Borchelt group’s overall research efforts to develop double-transgenic mice. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 33 of 42 29 This was, however, not a diversion or cessation of the group’s research looking for Aβ deposition, as USF argues, but a continuation of that research—while the requisite time passed to study the 12-month-old mice. As Dr. Borchelt explained, the group “made a tactical decision that we could not wait . . . to see whether our doubly transgenic mice would get amyloid plaques. It was going to be about another six to nine months before those mice [were old enough].” Ex. 2 at 31:9–13. So, given the necessary wait time and awareness of other researchers of the same topic, Ex. 2 at 31:14–17, the group conducted the related research leading to the 1996 Neuron Article, Ex. 15, in the interim. The 1996 Neuron Article examined, inter alia, younger mice brains for elevated levels of a certain Aβ peptide known at that time to be potentially indicative of Alzheimer’s disease pathology. Having found ratios indicating an elevated presence of the Aβ1-42(43) peptide, the Article’s results supported “the view that mutant presenilin acquires property(ies) that influence APP processing in a manner that results in elevated extracellular concentrations of Aβ1-42(43), a highly amyloidogenic peptide that is selectively deposited in the brains of individuals with AD and Down’s Syndrome.” Ex. 15 at 3. In other words, this research did not look for beta-amyloid deposition, but did find in younger mice elevated levels of a specific peptide (Aβ1-42(43)) that, as the ’094 patent acknowledged, was known to be “selectively deposited early in the FAD [familial Alzheimer’s disease] process” and that increased production of it “initiates” Alzheimer’s pathology. Ex. 10 at 5 (2:21–29). Thus, contrary to USF’s conclusions, the evidence of record clearly indicates that Dr. Borchelt’s group sought to find whether their double-transgenic mice evidenced beta-amyloid deposition in their brains from the outset of their research in 1995, and that the efforts leading to Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 34 of 42 30 the 1996 Neuron Article were a part of that research (even though the mice studied were necessarily too young to actually have Aβ deposits). E. DR. BORCHELT CONCEIVED HIS DOUBLE-TRANSGENIC MICE IN 1995, WITH THE FIRST MICE BORN IN APRIL 1996. By failing to properly acknowledge the goals and direction of the Borchelt group’s research, USF fails to recognize (nor even acknowledge contentions) that the Borchelt group conceived the claimed inventions of the ’094 patent in 1995, then diligently pursed that invention to an actual reduction to practice in 1997. Under the law, conception occurs when the inventor has an idea that was definite and permanent enough that one skilled in the art could understand the invention. See Fiers v. Revel, 984 F.2d 1164, 1169 (Fed. Cir. 1993). An idea is “definite and permanent” when the inventor has a specific, settled idea, a particular solution to the problem at hand, not just a general goal or research plan. See id.; Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1206 (Fed. Cir. 1989). Thus, “[t]he conception analysis necessarily turns on the inventor’s ability to describe his invention with particularity. Until he can do so, he cannot prove possession of the complete mental picture of the invention.” Burroughs Wellcome, 40 F.3d at 1228. Accordingly, “the inventor must prove his conception by corroborating evidence, preferably by showing a contemporaneous disclosure.” Id. Apart from Dr. Borchelt’s own testimony, e.g., Ex. 31, his lab notebook materials and supporting grant documents clearly support and corroborate that his group had “definite and permanent idea” of the claimed invention(s) of the ’094 patent in 1995. See Fiers, 984 F.2d at 1169. First, in 1995, Dr. Borchelt’s group had established founder lines for the mice that would be crossed to produce a double-transgenic mouse with a APPswe mutation and a A246E mutation (a PS1 mutation), as evidenced by his lab notebooks. See Ex. 21; Ex. 2 at 99:8–101:13; Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 35 of 42 31 Ex. 31 at 2–3 (¶¶ 9–10). Second, his NIH grant documents, likely prepared in late 1995 (Ex. 31 at 3 (¶ 12), further confirm that the Borchelt group sought these mice as models of the pathology of Alzheimer’s disease, which included beta-amyloid deposition. Ex. 22 at BOR_0670 (referencing that group had “already generated” founder lines). Specifically, in describing its grant work, the group was “confident that these efforts will lead to development of transgenic models of FAD, the study of which will clarify the mechanisms of disease.” Ex. 22 at BOR_0670 (emphases added). They further stated that their proposed models could be “used to explore the interactions of PS1/PS2 and APP in the pathogenesis of the disease.” Ex. 22 at BOR_0670 (emphasis added). Consistent with this, the Borchelt group first bred its double- transgenic mice in April 1996, intending to evaluate beta-amyloid deposition in their brains twelve months later. Ex. 2 at 126:13–127:8 (discussing cage card, Ex. 23 at BOR_0300–01). This evidence counters USF’s apparent assertion that it cannot be proven that Dr. Borchelt conceived prior to USF’s alleged reduction to practice in April 1997 because (1) “each and every claim of the ’094 patent” requires the mice in question to “exhibit accelerated Alzheimer’s Disease pathology,”10 Dkt. No. 101 at 10, and the government cannot show complete possession of this aspect of the invention at the alleged Borchelt conception. Dkt. No. 117 at 10–11. This is inaccurate. As discussed above, the evidence strongly indicates that Dr. Borchelt conceived of his mouse models in 1995 specifically to study the pathology of the disease, and in particular, bred his mice in the hopes that they would develop accelerated beta- amyloid deposits. See, e.g., Ex. 2 at 31:9–17. Thus, the evidence corroborates the Borchelt 10 Though such claim language often appears in the preamble of the claims-at-issue, the Court has found such language to be limiting, and thus a required element of the claims. See Dkt. No. 101 at 16–18. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 36 of 42 32 conception, specifically a complete “definite and permanent” idea of the invention(s) of the ’094 patent. See Fiers, 984 F.2d at 1169. F. THERE IS NO EVIDENCE THAT DR. BORCHELT HAD A CONFLICT OF INTEREST. The evidence of the 1995 Borchelt conception also counters USF’s unsupported contention that Dr. Borchelt had a conflict of interest by possibly participating in the review of AG14633 grant application. Dkt. No. 117 at 15. Though Dr. Borchelt was never questioned regarding these allegations, Ex. 2, the cited review occurred in a January 30, 1996 site visit, Ex. 3 at 82:13–84:7. Again, by 1995, Dr. Borchelt had already prepared his APPswe and presenilin (M146L, A246E, and ∆E9) founder lines and had begun preparing his grant application describing his intended double-transgenic mice. In contrast, USF’s application for the AG14633 grant does not describe any proposed double-transgenic mice with the APPswe mutation, Ex. 18, including Project IV cited by USF, Dkt. No. 117 at 4 (¶ 2). As Dr. Duff confirmed, that project relates chiefly to another APP transgenic mouse, the PDAP mouse, work that was never done. Ex. 1 at 179:15–183:12. The description of Project IV does not even mention an APPswe mutant mouse. Ex. 18 at 184–98 (HHS 00520–34). Thus, it is not clear what conflict of interest USF is alleging nor what information Dr. Borchelt improperly gained from the review that would be relevant to his conceived double-transgenic mice.11 The only evidence is that Dr. Borchelt worked in “the same field of research broadly” as the grant applicants. See Ex. 3 at 41:2. 11 Moreover, as discussed supra Part II.B (¶ 5), the only common researcher on the two papers (the 1997 Neuron Article and the 1998 Nature Paper) that disclose the double-transgenic mice (APPswe x PS) claimed in the ’094 patent, was Dr. Steven Younkin, whose potential conflicts of interest are never addressed in USF’s motion. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 37 of 42 33 G. DR. BORCHELT’S GROUP THEN DILIGENTLY PURSUED ITS CONCEIVED MOUSE MODEL TO A REDUCTION TO PRACTICE. The evidentiary record also clearly shows that the Borchelt group diligently worked to reduce its double-transgenic mouse models to practice, thereby solidifying their status as the first to invent the claims of the ’094 patent directed to the expression of APPswe in combination with any presenilin mutation. See Monsanto Co., 261 F.3d at 1369. As set forth in the government’s statement of material facts, see supra Part II.B, laboratory records show mice that were raised to one year of age and sacrificed in April 1997. This itself indicates that the Borchelt group was reasonably diligent in rearing and maintaining their mice for one year. The records then show that the brains of sacrificed mice were submitted for testing in early April 199712 as well, which ultimately showed accelerated beta-amyloid deposition in the double-transgenic mice as compared to parental mice. These results were first submitted to Neuron in June 1997 (approximately two months after testing began), and published in October 1997 in the 1997 Neuron Article, a clear documentation of the Borchelt group’s reduction to practice. Ex. 16 at 15; Teva, 661 F.3d at 1383 (providing standards for reduction to practice); Dkt. No. 117 at 7–8 (¶¶ 18–19). When the period of aging of 12-month-old mice is properly considered, this abbreviated timeline makes clear that the Borchelt group demonstrated “reasonable continuous diligence” in that its first invention was “not abandoned” or 12 This date indicates that the Borchelt group may have also had an actual reduction to practice (in addition to conception) ahead of the Hardy/Duff group, who alleges that its actual reduction to practice occurred on April 25, 1997. Dkt. No. 117 at 5 (¶ 7), 11. This is yet another factual dispute between the parties regarding the inventorship issue. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 38 of 42 34 “unreasonably delayed.” Perfect Surgical Techniques, Inc. v. Olympus Am., Inc., 841 F.3d 1004, 1009 (Fed. Cir. 2016).13 H. USF’S PURPORTED 1995 CONCEPTION LACKS ANY CORROBORATING EVIDENCE. In contrast to the Borchelt group’s conception, USF has failed to provide any corroborating evidence of its 1995 conception date. This issue was succinctly framed during Dr. Duff’s depositions when she confirmed, as a 30(b)(6) designee, that USF held no records of its purported 1995 conception, Ex. 1 at 97:23–98:18, and that the alleged conception merely consisted of a “discussion” of the invention at that time. Ex. 1 at 101:24–102:4; see also Ex. 1 at 97:9–98:22. This apparent vagueness is confirmed in the AG14633 grant application submitted by USF in 1994, which in Project IV, speaks of crossing mice transgenic-APP mice with mutant- presenilin mice, but APPswe is never specifically mentioned, Ex. 18 at 184–98, and according to Dr. Duff, the specified research was never conducted with the other APP transgenes that are mentioned. Ex. 1 at 179:15–183:12. As Dr. Morgan testified, the Hardy/Duff group “wrote that grant before the idea of this [double-transgenic mice] were developed, but by the time [it] got the grant [in 1996], this idea was well in place and underway.” Ex. 5 at 37:15–17. Even in the September 1996, Invention Disclosure Form, the Hardy/Duff group failed to specify use of 13 As the Federal Circuit has taught: In determining whether an invention antedates another, the point of the diligence analysis is not to scour the patent owner’s corroborating evidence in search of intervals of time where the patent owner has failed to substantiate some sort of activity. It is to assure that, in light of the evidence as a whole, “the invention was not abandoned or unreasonably delayed. Perfect Surgical Techniques, 841 F.3d at 1009 (quoting Monsanto, 261 F.3d at 1370). Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 39 of 42 35 APPswe. Ex. 19 at USF 02057; Ex. 1 at 64:22–65:24. All of this evidence points to the fact that USF cannot corroborate a conception in 1995, and for a large part of 1996. I. THE HARDY/DUFF GROUP’S EARLIEST RESEARCH BENCHMARKS REPEATEDLY OCCURRED SIGNIFICANTLY AFTER THE BORCHELT GROUP’S WORK. When all of the factual evidence is properly considered, the Borchelt group’s conception, creation of founder mice lines, initial breeding of double transgenic mice (with the APPswe and A246E (PS) mutation), and submission of results all significantly precede the same research benchmarks as the Hardy/Duff group, particularly when the corroborating evidence of each group is properly considered. See supra Part II.B. Thus, even if the Court determines both groups’ conception did not occur in 1995, the overwhelming evidence supports the conclusion that the Borchelt group was the first to conceive (and the first to invent under 35 U.S.C. § 102(g)) a double-transgenic mouse as set forth in claims 7, 8, 10, and 11 of the ’094 patent. The summary chart14 below elucidates this point: 14 The chart, as indicated, is provided for illustrative purposes and should not be considered as an admission to any corroborated and legally sufficient conception or reduction to practice by the Hardy/Duff group by the government. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 40 of 42 36 Event Borchelt Group Hardy/Duff Group Alleged Conception Late 1995 (corroborated by grant documents and founder-line work) 1995 (uncorroborated) APPswe/mutant PS founder lines Founder lines expressing APPswe created in March 1995 Founder lines expressing one of three presenilin mutations (including A246E and M146L) created in the fall of 1995 Founder line for APPswe obtained from Karen Hsiao (undated in record) First founder line for M146L created by Dr. Duff in “early summer of 1996” Double-transgenic mice (APPswe x. PS mutant) first born from founder- line cross First documented on April 13, 1996 First documented on August 21, 1996 Analysis of aged mouse brains for accelerated deposition Double-transgenic mouse (APPswe x A246E) sacrificed on April 9, 1997, brain prepared for testing on April 15, 1997 Results of 5.5 month aged mice with Aβ deposits reported on April 25, 1997 Research results showing accelerated deposition received for publication June 19, 1997 (the 1997 Neuron Article) July 24, 1997 (the 1998 Nature Paper) IV. CONCLUSION For the reasons stated above, USF’s motion should be denied as the overwhelming weight of the evidence demonstrates that (1) that the Borchelt group’s conception of the claimed inventions of the ’094 patent predates any corroborated date of conception by the Hardy/Duff group, (2) that the Borchelt group diligently reduced these claimed inventions to practice, and (3) that there is no evidence that Dr. Borchelt had a conflict of interest, as alleged by USF. Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 41 of 42 37 Respectfully submitted, JOSEPH H. HUNT Assistant Attorney General GARY L. HAUSKEN Director s/Walter W. Brown WALTER W. BROWN Senior Litigation Counsel Commercial Litigation Branch Civil Division Department of Justice Washington, D.C. 20530 walter.brown2@usdoj.gov Telephone: (202) 307-0341 Facsimile: (202) 307-0345 February 15, 2019 Attorneys for the United States Case 1:15-cv-01549-PEC Document 130 Filed 02/15/19 Page 42 of 42
