Opinion ID: 6112143
Heading Depth: 2
Heading Rank: 1

Heading: Written Description for the Dosage Limitation

Text: HEC argues that, as of the 2006 priority date, the inventors did not possess a 0.5 mg daily dose of fingolimod. It argues that, as of that date, 0.5 mg/day was considered too low to be effective to treat RRMS. It describes Novartis’s calculation of the 0.5 mg/day human dose as derived 6 Both parties wrongly assume that, if the 2006 priority application lacks sufficient written description of the ’405 patent’s claims, those claims are invalid. If the 2006 priority application lacks sufficient written description for the ’405 patent’s claims, the ’405 patent’s claims are not automatically rendered invalid; they are merely deprived of the 2006 priority date. See 35 U.S.C. § 119; see also Paice LLC v. Ford Motor Co., 881 F.3d 894, 906 (Fed. Cir. 2018) (“For claims to be entitled to a priority date of an earlierfiled application, the application must provide adequate written description support for the later-claimed limitations.”). Case: 21-1070 Document: 41 Page: 10 Filed: 01/03/2022 10 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. from the lowest disclosed dose in the rat EAE model described in the specification as “undisclosed mathematical sleights of hand.” Appellant’s Br. 7. And it argues that the Prophetic Trial, which lists a 0.5 mg daily dose along with two other dosages, does not provide sufficient written description of the 0.5 mg dose. Finally, it asserts that “blaze marks” directing a skilled artisan to the 0.5 mg daily dose are absent from the ’405 patent. We do not find HEC’s arguments convincing. The Prophetic Trial and the EAE model provide sufficient written description to show that, as of the priority date, the inventors possessed a 0.5 daily fingolimod dosage as claimed in the ’405 patent. The Prophetic Trial describes dosing RRMS patients with fingolimod hydrochloride at daily dosages of 0.5, 1.25, or 2.5 mg. ’405 patent col. 11 ll. 8–16. The Prophetic Trial’s disclosure of two other dosages does not detract from the written description of the claimed dose. Nor do disclosures of dosage ranges in other areas of the specification lead away from the claimed dose. The rat EAE model describes additional information which provides further written description for the 0.5 mg/day limitation. The EAE model describes a dosage of 0.3 mg/kg per week as effective to “fully block[] disease-associated angiogenesis and completely inhibit[] the relapse phases.” ’405 patent col. 10 ll. 64–col. 11 ll. 2. The district court credited the testimonies of Dr. Steinman and Dr. Jusko to arrive at the claimed 0.5 mg/day human dosage from the EAE experiment’s 0.3 mg/kg per week rat dosage. Those experts both testified that a skilled artisan would have converted the lowest daily rat dose described in the EAE experiment (0.3 mg/kg weekly) to a daily dose (0.042 mg/kg daily). J.A. 24 (citing J.A. 23325–26 (Tr. 747:6–748:19); J.A. 23443 (Tr. 865:12–24); J.A. 23482 (Tr. 904:2–18)). The district court found, again based on expert testimony, that a skilled artisan “would immediately recognize that 0.3 mg/kg weekly (0.042 mg/kg daily) in rats” is approximately 60% lower “than the lowest known effective Case: 21-1070 Document: 41 Page: 11 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 11 dose in the prior art (0.1 mg/kg daily).” J.A. 24–25 (citing J.A. 23440–41 (Tr. 862:25–863:21)). It found that a skilled artisan “would understand that the EAE results in the ’405 Patent therefore demonstrate that a proportionally lower dose (again, roughly 60% lower) could be effective in humans.” J.A. 25 (citing J.A. 23443–45 (Tr. 865:4–867:4); J.A. 23480–85 (Tr. 902:17–907:8)). It further found that a skilled artisan “would understand that the inventors translated the lowest dose that had ever been seen as effective from their EAE experiment (0.3 mg/kg once per week) to the 0.5 dose.” J.A. 25 (citing J.A. 23356–57 (Tr. 778:25–779:14)). HEC attacks the expert testimony underlying the district court’s determination that the EAE experiment describes a 0.5 mg daily human dose as “undisclosed mathematical sleights of hand.” Appellant’s Br. 7. We disagree. A “disclosure need not recite the claimed invention in haec verba.” Ariad, 598 F.3d at 1352. The disclosure need only “clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed.” Id. at 1351. To accept HEC’s argument would require us to ignore the perspective of the person of ordinary skill in the art and require literal description of every limitation, in violation of our precedent. We find no clear error in the district court’s reliance on expert testimony in finding description of the 0.5 mg daily human dose in the EAE experiment results. We also reject HEC’s argument that the ’405 patent does not have necessary “blaze marks” pointing to the 0.5 mg daily dose. “Blaze marks” directing an investigator of ordinary skill in the art to the claimed species from among a forest of disclosed options are not necessary in this case. In cases where the specification describes a broad genus and the claims are directed to a single species or a narrow subgenus, we have held that the specification must contain “‘blaze marks’ that would lead an ordinarily skilled investigator toward such a species among a slew of competing Case: 21-1070 Document: 41 Page: 12 Filed: 01/03/2022 12 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. possibilities.” Novozymes v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349 (Fed. Cir. 2013). “Blaze marks” are not necessary where the claimed species is expressly described in the specification, as the 0.5 mg daily dosage is here. See, e.g., Snitzer v. Etzel, 465 F.2d 899, 902 (C.C.P.A. 1972) (finding that interference counts directed to the activation of a glass laser with trivalent ytterbium ions were adequately described by a specification listing fourteen materials which may be used as active laser ingredients, including trivalent ytterbium, and noting that “there would seem to be little doubt that the literal description of a species provides the requisite legal foundation for claiming that species”). The ’405 patent does not contain the laundry-list-type disclosures that we have found require guidance to direct a skilled artisan to the claimed species—it contains the Prophetic Trial listing three doses, 0.5, 1.25, and 2.5 mg/day. While other sections of the specification disclose larger ranges of potential doses for S1P receptor modulators, e.g., 0.1 to 100 mg/day doses, those disclosures do not diminish the literal description of the 0.5 mg/day dose in the Prophetic Trial. All described dose ranges include the 0.5 mg/day dose. And smaller dosage ranges, such as 0.5–30 mg/day, are disclosed for fingolimod hydrochloride. Even if blaze marks were required in this case, the Prophetic Trial and 0.5–30 mg/day dosage range would provide a skilled artisan more than sufficient guidance to direct them to the claimed 0.5 mg/day dose. Much of HEC’s argument is directed to its assertion that no one, including the inventors, knew that a 0.5 mg/day dose would be effective as of the 2006 priority date. That argument fails for two reasons. First, efficacy is not a requirement of the claims. The claims require only administration of a 0.5 mg/day dose for, inter alia, treatment purposes. The district court found that the purpose limitations are adequately described, and HEC has not appealed that finding. Thus, cases such as Nuvo Pharms., 923 F.3d 1368, in which this court found that claims directed to an Case: 21-1070 Document: 41 Page: 13 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 13 amount of uncoated PPI that is effective to raise the gastric pH to at least 3.5 were not adequately described by a specification that “provides nothing more than the mere claim that uncoated PPI might work” where skilled artisans “would not have thought it would work,” are distinguishable. See id. at 1381. Second, as explained above, the EAE model provides evidence that the inventors knew that a 60% lower dose would be effective. For these reasons, we find no clear error in the district court’s holding that the 0.5 mg/day dosage limitation is adequately described. The district court’s holding is supported by the specification and ample expert testimony interpreting that specification. B. Written Description for the Negative Limitation HEC argues that there is no written description of the negative limitation because the ’405 specification contains no recitation of a loading dose “or its potential benefits or disadvantages at all.” Appellant’s Br. 40. It further argues that the district court’s finding of written description of the negative limitation within the ’405 specification contradicts the district court’s finding that Kappos 2006, which is similarly silent as to loading doses, does not anticipate the claims. We find both arguments unavailing. It is well established that there is no “new and heightened standard for negative claim limitations.” Inphi Corp. v. Netlist, Inc., 805 F.3d 1350, 1356 (Fed. Cir. 2015). We are aware of no case that suggests otherwise. And, while HEC asserts that “[i]t is well-settled law that silence alone cannot serve as a basis for” a negative limitation, Appellant’s Br. 41, HEC identifies no case that actually supports that proposition. To the contrary, we repeatedly have resisted imposition of heightened written description standards for negative limitations, such as that urged by HEC. For example, in Santarus, Inc. v. Par Pharmaceutical, Inc., we found that claims directed to a method of Case: 21-1070 Document: 41 Page: 14 Filed: 01/03/2022 14 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. treatment with a pharmaceutical composition containing no sucralfate were adequately described by a specification that explained that, although sucralfate is “possibly the ideal agent for stress ulcer prophylaxis,” it was known to have occasional adverse effects. 694 F.3d 1344, 1350–51 (Fed. Cir. 2012). In Santarus, as in this case, there was expert testimony providing a person of ordinary skill’s understanding of the patent specification. See id. at 1351. The expert testimony in Santarus showed that “a person of ordinary skill in this field . . . would have understood from the specification that disadvantages of sucralfate may be avoided by the [claimed] formulation.” Id. We explained that “[n]egative claim limitations are adequately supported when the specification describes a reason to exclude the relevant limitation.” Id. We did not hold that a specification must describe a reason to exclude a negative limitation. A specification that describes a reason to exclude the relevant negative limitation is but one way in which the written description requirement may be met. In In re Bimeda Research. & Development Ltd., we held that a claim that excluded a specific anti-infective, acriflavine, was not adequately described by a disclosure that was inconsistent with the exclusion of acriflavine but not other anti-infectives or antibiotics. 724 F.3d 1320, 1324 (Fed. Cir. 2013). The claim at issue in Bimeda was directed to a method of preventing mastitis in dairy cows by sealing the teat canal of a cow’s mammary gland with a seal formulation that excludes acriflavine. Other claims in the same patent excluded all anti-infective agents. We noted that the patent repeatedly distinguished the invention as able to prevent mastitis without the use of antibiotics. Based on the written description’s consistent description of the invention’s non-antibiotic approach to preventing mastitis, we concluded that the patent’s disclosure was “inconsistent with a claim which excludes acriflavine, but not the presence of other antiinfectives or antibiotics.” Id. (citation and quotation marks omitted). We did not require that the Case: 21-1070 Document: 41 Page: 15 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 15 specification describe a reason to exclude acriflavine specifically, but, rather, found only that a negative limitation which is inconsistent with the disclosure is not adequately described. In Inphi, we confirmed that the written description requirement is satisfied where “‘the essence of the original disclosure’ conveys the necessary information—‘regardless of how it’ conveys such information, and regardless of whether the disclosure’s ‘words [a]re open to different interpretation[s].’” 805 F.3d at 1354 (quoting In re Wright, 866 F.2d 422, 424–25 (Fed. Cir. 1989) (citation and internal quotation marks omitted)). We explained that “Santarus simply reflects the fact that the specification need only satisfy the requirements of § 112, paragraph 1 as described in this court’s existing jurisprudence[.]” Id. at 1356. And we noted that the “‘reason’ required by Santarus is provided, for instance, by properly describing alternative features of the patented invention.” Id. (citing In re Johnson, 558 F.2d 1008, 1019 (C.C.P.A. 1977)). In Inphi, we found that substantial evidence supported the Patent Trial and Appeal Board’s (“Board”) finding that a negative limitation which had been added during prosecution (“DDR chip selects that are not CAS, RAS, or bank address signals”) was adequately described by an original specification which did not expressly articulate a reason to exclude RAS and CAS signals. We found the Board’s decision was supported by evidence of (1) standards set by the Joint Electron Device Engineering Council, a global standard setting body for the microelectronics industry, incorporated by reference in the patent, which specify that DDR signals, including CS, RAS, CAS, and bank address signals, are distinct from each other; (2) a table in the specification which excludes RAS and CAS signals; and (3) various passages from the specification, including a figure which distinguishes chip select signals, command signals (including RAS and CAS signals) and bank address signals. We concluded that the specification’s disclosure of Case: 21-1070 Document: 41 Page: 16 Filed: 01/03/2022 16 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. alternative features was sufficient to satisfy the written description standard for the negative limitation. Id. at 1357. In Nike, Inc. v. Adidas AG, we reiterated that Santarus did not create a heightened standard for written description of negative limitations. 812 F.3d 1326, 1348 (Fed. Cir. 2016), overruled on other grounds by Aqua Prods., Inc. v. Matal, 872 F.3d 1290 (Fed. Cir. 2017). We stated that negative limitations, like all other limitations, are held to “the customary standard for the written description requirement.” Id. In Nike, we found a limitation of “flat knit edges,” which Adidas characterized as a negative limitation, was adequately described by three figures in the specification depicting the claimed textile element which Nike’s expert opined could be made using flat knitting in contrast to another figure’s textile element which is formed using a circular knitting machine. Id. at1348–49. Similarly, in Erfindergemeinschaft Uropep GBR v. Eli Lilly & Co., Judge Bryson, sitting by designation in the Eastern District of Texas, explained that the law does not require that the disclosure explain a negative limitation. 276 F. Supp. 3d 629, 657–58 (E.D. Tex. 2017), aff’d, 739 F. App’x 643 (Fed. Cir. 2018). Judge Bryson explained, citing Bimeda, that “[w]hat is prohibited is a negative limitation that is contrary to the thrust of the invention.” Id. at 658. He noted that “a patentee can choose to claim any particular embodiments identified in the specification and exclude others, without explanation, as long as the claim does not indicate to persons of skill that it covers embodiments inconsistent with, and therefore unsupported by, the disclosure.” Id. In asserting that “silence alone cannot serve as a basis for” a negative limitation, Appellant’s Br. 41, HEC attempts to create a new heightened written description standard for negative limitations. In doing so, it ignores a central tenet of our written description jurisprudence— that the disclosure must be read from the perspective of a Case: 21-1070 Document: 41 Page: 17 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 17 person of skill in the art—as well as precedent stating that the disclosure need not describe a limitation in haec verba. See, e.g., All Dental Prodx, LLC v. Advantage Dental Prod., Inc., 309 F.3d 774, 779 (Fed. Cir. 2002) (“[T]he failure of the specification to specifically mention a limitation that later appears in the claims is not a fatal one when one skilled in the art would recognize upon reading the specification that the new language reflects what the specification shows has been invented.” (citing Eiselstein v. Frank, 52 F.3d 1035, 1039 (Fed. Cir. 1995)); see also Ariad, 598 F.3d at 1351. In other words, context and the knowledge of those skilled in the art matter. And, as the Supreme Court has made clear, when assessing what the written description reveals to a skilled artisan, common sense also matters. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) (holding that, in an obviousness analysis, “[r]igid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it”). The dissent notes that the Manual of Patent Examining Procedure (“MPEP”) 7 states: “The mere absence of a positive recitation is not a basis for an exclusion.” MPEP § 2173.05(i). As the dissent puts it—“silence alone is insufficient.” Dissent at 4. Both the MPEP and the dissent are correct in their statement of the law: the “mere absence of a positive recitation” is not enough and “silence alone is insufficient.” But the dissent, like HEC, ignores that it is how a skilled artisan reads a disclosure that matters. Written description may take any form, so long as a skilled artisan would read the disclosure as describing the claimed invention. Our case law makes clear that “[c]ompliance with the written description requirement is essentially a fact-based 7 The MPEP is not binding on this court but may be persuasive. Case: 21-1070 Document: 41 Page: 18 Filed: 01/03/2022 18 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. inquiry that will ‘necessarily vary depending on the nature of the invention claimed.’” Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 963 (Fed. Cir. 2002) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562 (Fed. Cir. 1991)). The MPEP similarly provides for written description in various forms. In addition to stating that the “mere absence of a positive recitation” is not enough, the MPEP also correctly states that no specific form of disclosure is required and provides for implicit written description. MPEP § 2173.05(i) states that “a lack of literal basis in the specification for a negative limitation may not be sufficient to establish a prima facie case for lack of descriptive support.” And MPEP § 2163 states that “newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” MPEP § 2163 (emphasis added). What is critical is how a person of skill in the art would read the disclosure—not the exact words used. HEC and the dissent urge us to elevate form over substance by creating a new rule that a limitation which is not expressly recited in the disclosure is never adequately described, regardless of how a skilled artisan would read that disclosure. As we have several times before, we reject the invitation to create a heightened written description standard for negative limitations. As with all other limitations, the negative limitation here must be accompanied by an original disclosure which conveys to a person of ordinary skill that the inventor was in possession of the claimed invention. See Ariad, 598 F.3d at 1351. And, as in all other written description challenges, HEC was required to show by clear and convincing evidence that the negative limitation was not adequately described. The district court did not clearly err in finding that HEC failed to do so. In determining that there is adequate written description of the negative limitation, the district court correctly, and quite carefully, conducted “an objective inquiry into the four corners of the specification from the perspective of Case: 21-1070 Document: 41 Page: 19 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 19 a person of ordinary skill in the art” as required by our precedent. See Ariad, 598 F.3d at 1351. We review the evidence cited by the district court below and discern no clear error in the court’s analysis or conclusions. The Prophetic Trial describes giving RRMS patients fingolimod hydrochloride “at a daily dosage of 0.5, 1.25 or 2.5 mg p.o.” ’405 patent col. 11 ll. 8–9. It further states that: “Initially patients receive treatment for 2 to 6 months.” Id. col. 11 ll. 13–14. Dr. Steinman, one of Novartis’s expert witnesses, testified from the perspective of a skilled artisan that, if the Prophetic Trial included a loading dose, the patent would explicitly state as much: “[T]here were two places where if there were going to be a loading dose, you would explicitly state it. .... So the first place one might explicitly say there was—there was a preceding loading dose is when you described the daily dosage, the reason being a loading dose would occur before the first daily dose. The second place is even more dramatic, because they say, “Initially patients received treatment for 2 to 6 months.” So now they’re really zooming in on Day 1, what is that treatment, it’s a daily dose of 0.5. So there were two perfectly logical places that if there was going to be a loading dose, it would have been stated. .... That’s where you would put it if you were going to give a loading dose. J.A. 23343 (Tr. 765:2–25). Similarly, Dr. Fred Lublin, Ph.D., another expert testifying for Novartis, testified that a person of skill in the art Case: 21-1070 Document: 41 Page: 20 Filed: 01/03/2022 20 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. “would have viewed the patent as a document, as a complete document, that should give you all the information you need to carry out the claims, and that information of having a loading dose is not there, and what’s instead there is examples of daily dose, daily dose, daily dose.” J.A. 22791 (Tr. 213:6–15). Dr. Lublin testified that a “loading dose is a greater than normal dose that you give until you return to a maintenance dose” and a loading dose is “not a daily dose.” J.A. 22792 (Tr. 214:1–9). He further testified that “[o]ne would expect in a patent that if there was going to be a loading dose, it would be specified.” J.A. 22793 (Tr. 215:5–8). And a third expert testifying for Novartis, Dr. Jusko, similarly testified that, from the perspective of a person of skill in pharmacology, the Prophetic Trial has a “specified initial regimen that does not include a loading dose.” J.A. 23442 (Tr. 864:14–16). The district court credited this expert testimony, as well as the testimony from HEC’s own expert, Dr. Paul Hoffman, M.D., who agreed that “a loading dose is a higherthan-therapeutic level dose, usually given . . . as the first dose.” J.A. 23125 (Tr. 547:14–18); J.A. 27. Based on that evidence, the court concluded that the “absence of an immediately preceding loading dose from the specification, and from the Prophetic Trial, would tell a person of skill that loading doses are excluded from the invention.” J.A. 26. We discern no clear error in that finding. The district court further noted that the rat EAE experiment does not describe a loading dose. J.A. 26. It again credited the testimony of multiple expert witnesses who testified that the EAE model did not include a loading dose. J.A. 26. Dr. Jusko, in response to a question about whether there are any loading doses in the EAE model, stated: “Not that I’m aware of.” J.A. 22793 (Tr. 215:16–21). Dr. Steinman similarly testified that no loading dose was used in the EAE experiment. J.A. 23345 (Tr. 767:3–5). HEC’s own expert witness, Dr. Hoffman, testified that the EAE model does not talk about a loading dose. J.A. 23209 (Tr. 631:18–22). Case: 21-1070 Document: 41 Page: 21 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 21 Based on both the specification’s disclosure of the rat EAE model and the ample expert testimony providing evidence of how a person of ordinary skill would read that disclosure, the district court concluded that the “EAE example discloses a dosing regimen which does not involve a loading dose.” J.A. 27. Finally, the district court noted that, while the patent “describes alternative dosing regimens, like ‘intermittent dosing,’ [it] does not describe loading doses.” J.A. 27. The district court concluded that the “EAE model and the Prophetic Trial . . . both indicate to a person of ordinary skill that the claimed invention did not include the administration of a loading dose.” J.A. 37–38. We are not left with the “definite and firm conviction” that the district court made a mistake in coming to this conclusion. See Nuvo Pharms., 923 F.3d at 1376 (quoting Scanner Techs., 528 F.3d at 1374). To the contrary, the district court’s conclusion appears wholly correct. To arrive at the opposite conclusion would require us to disregard the perspective of a person of skill in the art—something our precedent simply does not allow. See Ariad, 598 F.3d at 1351. We also find unpersuasive HEC’s argument that the district court’s written description decision contradicts its determination that the ’405 patent is not anticipated by Kappos 2006. HEC notes that neither Kappos 2006 nor the ’405 patent’s specification explicitly state that a loading dose should not be administered. But HEC’s argument ignores the differences between the two district court findings and ignores the differences between the disclosures of Kappos 2006 and the ’405 specification. As a granted patent, the ’405 patent is presumed valid. Thus, it is also presumed to have a complete written description. See Nat’l Recovery Techs., Inc. v. Magnetic Separation Sys, Inc., 166 F.3d 1190, 1195 (Fed. Cir. 1999) (“The presumption of validity includes a presumption that the patent complies with § 112.”). No such presumption Case: 21-1070 Document: 41 Page: 22 Filed: 01/03/2022 22 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. applies to disclosures of a prior art reference that is not itself a granted patent, such as Kappos 2006. Further, the perspective of a person of skill in the art is important in both the written description and the anticipation inquiries. And, in this case, the district court credited the testimony of two expert witnesses, Dr. Lublin and Dr. Steinman, who testified that a person of skill in the art would not presume that the Kappos 2006 abstract was complete. J.A. 30 (citing J.A. 22782 (Tr. 204:12–19) (Dr. Lublin testifying that abstracts “have to by design” leave out information describing clinical trials); J.A. 23475 (Tr. 897:1–5) (Dr. Steinman testifying that “an abstract, like a press release, like any kind of announcement, is inherently incomplete,” while “a publication and a patent are presumed complete”)). Thus, although neither the ’405 specification nor Kappos 2006 include the phrase “loading dose,” it was not clear error for the district court to find that a skilled artisan would read the specification as not including a loading dose and would read Kappos 2006 as silent on the presence or absence of a loading dose. Differences between the ’405 patent’s specification and Kappos 2006 justify the district court’s findings that the specification describes the absence of a loading dose while Kappos 2006 does not anticipate that negative limitation. The specification includes the Prophetic Trial, which the district court found “describes giving a ‘daily dosage of 0.5 . . . mg’ fingolimod to treat RRMS, started ‘initially.’” J.A. 26. The district court found that, “[o]n this record, starting with a daily dose plainly implies that there is no loading dose.” J.A. 27. Kappos 2006 consists of two paragraphs describing a planned clinical trial and, with respect to dosing, states only that “[a]pproximately 1.100 patients . . . are being randomised in a 1:1:1 ratio to once-daily fingolimod 1.25 mg, fingolimod 0.5 mg, or placebo, for up to 24 months.” J.A. 24723–24. Kappos 2006 nowhere says that the daily fingolimod dosage should be “initially” administered. Thus, differences between Kappos 2006 and the ’405 Case: 21-1070 Document: 41 Page: 23 Filed: 01/03/2022 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. 23 patent justify the district court’s conclusions that Kappos 2006 does not anticipate the claims and the ’405 specification adequately describes the claims. The dissent takes umbrage with the district court’s finding that the “Prophetic Trial describes giving a ‘daily dosage of 0.5 . . . mg’ fingolimod to treat RRMS, started ‘initially’” because the ’405 patent says “[i]nitially, patients receive treatment for 2 to 6 months.” Dissent at 6–7; J.A. 26; ’405 patent col. 11 ll. 13–14. The dissent would find that the “word ‘initially’ is not modifying the daily dosage; it is modifying the initial length of treatment in this example.” Dissent at 6–7. The dissent, thus, would substitute its own factual findings for those of the district court. But, if the 2–6 month “initial” dose does not differ in any way from the previously described daily doses, the language, used in context, must exclude a loading dose. As we have already explained, the district court did not clearly err in finding that the “Prophetic Trial describes giving a ‘daily dosage of 0.5 . . . mg’ fingolimod to treat RRMS, started ‘initially.’” J.A. 26. And we are not free to substitute our own factual findings for those of the district court absent clear error because “a district court judge who has presided over, and listened to, the entire pro- ceeding has a comparatively greater opportunity to gain the necessary ‘familiarity with specific scientific problems and principles,’ . . . than an appeals court judge who must read a written transcript or perhaps just those portions referenced by the parties.” Teva Pharms. USA, Inc. v. Sandoz, Inc., 574 U.S. 318, 319 (2015) (quoting Graver Tank & Mfg. Co. v. Linde Air Prods. Co., 339 U.S. 605, 610 (1950)). The dissent also asserts that, on this record, the term “daily dose” would not convey to a skilled artisan that no loading dose should be used. Dissent at 7–8. But the district court’s decision did not rely only on the term “daily dose.” Rather, as noted above, the district court found that “starting with a daily dose plainly implies that there is no loading dose,” as a loading dose is a larger-than-daily dose. J.A. 27 (emphasis added). We need not, and do not, go Case: 21-1070 Document: 41 Page: 24 Filed: 01/03/2022 24 NOVARTIS PHARMACEUTICALS v. ACCORD HEALTHCARE INC. further than the district court to make findings about the term “daily dose.” The dissent’s assertion to the contrary and allegation that we “tease[] an entirely new claim limitation out of an entirely common term, relegating the legal determination of a term’s meaning to the backseat of an expert’s post-hoc rationalization” is, frankly, baffling. See Dissent at 8. Written description in this case, as in all cases, is a factual issue. In deciding that the district court did not clearly err in finding written description for the negative limitation in the ’405 patent, we do not establish a new legal standard that silence is disclosure, as the dissent asserts. Instead, we merely hold that, on this record, the district court did not clearly err in finding that a skilled artisan would read the ’405 patent’s disclosure to describe the “absent an immediately preceding loading dose” negative limitation.