Merck Serono S.A. v. Twi Pharmaceuticals, Inc.

• Court: Court of Appeals for the Federal Circuit
• Decided: October 30, 2025
• Docket: 25-1463
• Status: Unpublished

Opinion

Case: 25-1463 Document: 41 Page: 1 Filed: 10/30/2025

NOTE: This disposition is nonprecedential.

United States Court of Appeals for the Federal Circuit ______________________

MERCK SERONO S.A., Appellant

v.

TWI PHARMACEUTICALS, INC., Appellee ______________________

2025-1463, 2025-1464 ______________________

Appeals from the United States Patent and Trademark Office, Patent Trial and Appeal Board in Nos. IPR2023- 00049, IPR2023-00050. ______________________

Decided: October 30, 2025 ______________________

MARK CHRISTOPHER FLEMING, Wilmer Cutler Pickering Hale and Dorr LLP, Boston, MA, argued for appellant. Also represented by JAMES M. LYONS, EMILY R. WHELAN; DAVID B. BASSETT, GARY M. FOX, JENNIFER L. GRABER, New York, NY; HELENA RACHAEL MILLION-PEREZ, Denver, CO; NORA N. XU, Washington, DC.

PHILIP D. SEGREST, JR., Husch Blackwell LLP, Chicago, IL, argued for appellee. Also represented by DONALD J. MIZERK; STEPHEN REID HOWE, Milwaukee, WI. Case: 25-1463 Document: 41 Page: 2 Filed: 10/30/2025

______________________

Before HUGHES, LINN, and CUNNINGHAM, Circuit Judges. LINN, Circuit Judge. This case is a companion case to Merck Serono S.A. v. Hopewell Pharma Ventures, Inc., No. 2025-1210, -1211, (Fed. Cir. argued July 11, 2025; decided Oct. 30, 2025) (hereinafter Hopewell), argued on the same day and de- cided contemporaneously herewith. Merck Serono S.A. (“Merck”) appeals the determina- tions by the Patent Trial and Appeal Board (“Board”) in two inter partes reviews (“IPR”) that claims 36, 38, 39, and 41–48 of Merck’s U.S. Patent No. 7,713,947 (“’947 patent”) and claims 17, 19–20, and 22–29 of Merck’s U.S. Patent No. 8,377,903 (“’903 patent”) are unpatentable as obvious (col- lectively “patents-in-suit”). TWi Pharms., Inc. v. Merck Serono SA, IPR2023-00049 (P.T.A.B. Dec. 18, 2024) (ad- dressing U.S. Pat. No. 7,713,947) (hereinafter “FWD”); TWi Pharms., Inc. v. Merck Serono SA, IPR2023-00050 (P.T.A.B. Dec. 18, 2024) (addressing U.S. Pat. No. 8,377,903). The parties argue all claims of both pa- tents together, and, unless otherwise stated, we reference the Board’s FWD in IPR2023-00049 exclusively in this opinion. Because Bodor is prior art based on our analysis in Hopewell, and because we see no legal or factual errors in the Board’s analysis in this case, we affirm. BACKGROUND I The background of the development of the patents-in- suit is largely the same as laid out in Hopewell and we refer the parties thereto for a more comprehensive statement of facts. In brief, Merck partnered with generic manufacturer and formulator IVAX to develop oral cladribine to treat Case: 25-1463 Document: 41 Page: 3 Filed: 10/30/2025

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multiple sclerosis (“MS”), a chronic disease of the central nervous system. Under their joint research agreement, Merck would “‘conduct clinical trials’ to determine ‘the dose, safety, and/or efficacy’” of cladribine oral tablets, and IVAX would “develop an oral dosage formulation of [cladribine] in tablet or capsule form suitable for use in clinical trials and commercial sale.” J.App’x 6076 (Munafo Decl. at ¶¶ 24–25). On October 14, 2004, IVAX employees Drs. Bodor and Dandiker filed PCT application PCT/US2004/009387, 1 which later became U.S. Patent No. 7,888,328 (“Bodor”), ti- tled “Oral Formulations of Cladribine.” Bodor 2 includes the following key passage that the parties refer to as the “seven-line disclosure”: At the present time, it is envisioned that, for the treatment of multiple sclerosis, 10 mg of cladribine in the instant complex cladribine-cyclodextrin complex in the in- stant solid dosage form would be adminis- tered once per day for a period of five to seven days in the first month, repeated for another period of five to seven days in the second month, followed by ten months of no treatment. Bodor, col. 13, ll. 19–25. 3

1 The PCT application is the primary reference in the companion Hopewell case. For purposes of this appeal, the PCT Application and the U.S. Patent to Bodor are substan- tively identical. 2 This opinion refers to the U.S. Patent as “Bodor,” and refers to its author Dr. Bodor as “Dr. Bodor.” 3 In the companion 2025-1210 case, the parties refer to the same disclosure as the “six-line disclosure” or, Case: 25-1463 Document: 41 Page: 4 Filed: 10/30/2025

II Within a year of Bodor’s filing, on December 22, 2004, Merck filed the applications to which the patents-in-suit claim priority. Both patents list as inventors: Drs. De Luca, Ythier, Munafo, and Lopez-Bresnahan (collectively, “named inventors”), all of whom were employees of Serono and, in at least some way, were a part of the development team that developed the claimed oral cladribine regimen. The ’947 patent issued in 2010, and the ’903 patent issued in 2013. In representative claim 36 of the ’947 patent, Merck claimed the dosing regimen as follows: 36. A method of treating multiple sclerosis compris- ing the oral administration of a formulation compris- ing cladribine following the sequential steps below: (i) an induction period lasting from about 2 months to about 4 months wherein said formulation is orally administered and wherein the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) a cladribine-free period lasting from about 8 months to about 10 months, wherein no cladribine is administered; (iii) a maintenance period lasting from about 2 months to about 4 months, wherein said formulation is orally administered and wherein the total dose of cladribine reached at the end of the maintenance pe- riod is about 1.7 mg/kg; (iv) a cladribine-free period wherein no cladribine is administered.

sometimes, the “one-line disclosure.” All of these charac- terizations refer to the same quoted language in Bodor. Case: 25-1463 Document: 41 Page: 5 Filed: 10/30/2025

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Claim 17 of the ’903 patent is substantively identical for purposes of this appeal. Dependent claims in both patents further limit “the total dose of cladribine reached at the end of the induction period” to “about 1.7mg/kg.” ’947 patent, Cl. 39; ’903 patent, Cl. 20.

Claim 47 in the ’947 patent depends from claim 36, and adds the limitation: “wherein the steps (iii) to (iv) are re- peated at least one or two times.” Claim 48 in the ’947 pa- tent also depends from claim 36, adds the limitation “wherein the formulation is administered in combination with interferon-beta.” The limitations are identically ech- oed in claims 28 and 29 (both depending from claim 17) of the ’903 patent.

The parties argue all claims of both patents together. III TWi Pharmaceuticals, Inc. (“TWi”) filed IPRs challeng- ing claims 36, 38, 39, and 41–48 of the ’947 patent in IPR2023-00049, and challenging claims 17, 19–20, and 22– 29 of the ’903 patent in IPR2023-00050 on three grounds: anticipation over Bodor; obviousness over Bodor and the knowledge of persons of ordinary skill; and obviousness over Bodor and Rice. 4 The challenged claims here largely overlap with those held unpatentable in the companion Hopewell appeal, except for claims 47 and 48 of the ’947 patent and claims 28 and 29 of the ’903 patent, which were not challenged in Hopewell. Rice, incorporated by reference into Bodor, col. 13, ll. 5–8, is a publication discussing a double-blind clinical study on subcutaneous administration of cladribine on

4 Rice et al., “Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial.” Neu- rology, 54(5): 1145-55 (2000). J.App’x 2254–64. Case: 25-1463 Document: 41 Page: 6 Filed: 10/30/2025

patients with the progressive form of MS. Rice disclosed treatment cycles of administering placebo or cladribine at 0.07mg/kg per day for five consecutive days every four weeks for either two or six cycles, followed by placebo for a total of eight cycles. J.App’x 2254–56. Rice included an open label follow-up retreatment phase for patients who showed “evidence of disease progression” and “fulfilled the hematologic dosing criteria” with further doses adminis- tered “at least 12 months” after the last dose of cladribine. J.App’x 2255. In its FWD, the Board held that all challenged claims were unpatentable as obvious over Bodor in view of Rice and not unpatentable as anticipated. The Board did not reach the alternative ground that the claims were un- patentable as obvious over Bodor in light of the knowledge of persons of ordinary skill in the art. J.App’x 65 n.19. The Board also noted that “Patent Owner raises no separate ar- gument for any of the dependent claims.” J.App’x 64. The Board first considered whether Bodor was prior art. Because Bodor names entirely different authors than the named inventors, the Board shifted the burden of pro- duction to patentee “to come forward with evidence suffi- cient to support the proposition that Bodor is not prior art.” J.App’x 23 (citing, inter alia, Google LLC v. IPA Techs. Inc., 34 F.4th 1081, 1085–86 (Fed. Cir. 2022)). To show that Bodor was not prior art, the Board sought evidence that the seven-line disclosure in Bodor was not “by another,” which the Board said required “credible and corroborated evidence that each named inventor [of the pa- tents] Munafo, Lopez-Bresnahan, Ythier, and De Luca pro- vided an inventive contribution to the 7-line dosing regimen.” J.App’x 23; see also J.App’x 26 (requiring evi- dence “that the disclosure was invented by the same ‘in- ventive entity’ as the ’947 patent’s challenged claims”). The Board rejected patentee’s testimony from named in- ventor Dr. Munafo that the Board said was only enough to Case: 25-1463 Document: 41 Page: 7 Filed: 10/30/2025

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show that “the team at Serono” contributed to the disclo- sure, but not what “any one of the named inventors, indi- vidually or as a group” contributed. J.App’x 24 (cleaned up). On the merits, the Board held that the instituted claims were unpatentable as obvious over Bodor and Rice. The Board held that the seven-line disclosure “teaches or suggests” the induction period and cladribine-free period. J.App’x 40. The Board also found persuasive the testimony of Dr. Greenberg at J.App’x 2086–87 (¶¶ 110–113) that it summarized as follows: “MS is a disease without a cure that typically needs ongoing treatment and, reading Bodor in that context, [an ordinary artisan] would have thought to re-administer cladribine after the specified cladribine- free period.” J.App’x 40. Moreover, the Board found that it would have been obvious to follow the maintenance phase with another cladribine-free period, based on Rice’s following each treatment phase with a cladribine-free pe- riod and on Dr. Greenberg’s testimony that such a period would help control drug toxicity. J.App’x 46–47; see J.App’x 2132–33 (Dr. Greenberg testimony at ¶¶ 196–98); J.App’x 2093 (¶ 124); J.App’x 2087–89 (¶¶ 113–18). The Board found a reason to combine the references to reach the claimed induction, cladribine-free, retreatment and cladribine-free periods and a likelihood of success in such combination because “the symptoms of MS were likely to relapse and repeat” and ordinary artisans would logi- cally repeat Bodor’s induction dosing in the retreatment phase, J.App’x 49, at least for those patients who showed signs of relapse, J.App’x 51. Merck timely appealed. We have jurisdiction to review the Board’s final written decision after an IPR under 28 U.S.C. § 1295(a)(4)(A) and 35 U.S.C. §§ 141(c). Case: 25-1463 Document: 41 Page: 8 Filed: 10/30/2025

DISCUSSION I Whether a reference is a work “by another” for pur- poses of prior art is a question of law reviewed de novo, based on underlying facts reviewed for substantial evi- dence. Google LLC, 34 F.4th at 1085; Allergan, Inc. v. Apo- tex Inc., 754 F.3d 952, 969 (Fed. Cir. 2014) (“The question of whether a reference is a work of others for the purposes of § 102(a) is, like that of inventorship, a question of law based on underlying facts.”). We review whether the Board applied the correct law, a legal determination, de novo. Princeton Vanguard, LLC v. Frito-Lay N. Am., Inc., 786 F.3d 960, 964 (Fed. Cir. 2015). Obviousness is a question of law based on underlying facts reviewed for substantial evidence. Voice Tech Corp. v. Unified Pats., LLC, 110 F.4th 1331, 1342 (Fed. Cir. 2024). II Most of Merck’s arguments here parallel those it made in the related Hopewell case. Merck first argues that the Board applied an incorrect legal rule requiring complete identity of inventive entity to exclude a reference as the in- ventor’s own work, whereas Applied Materials, Inc. v. Gem- ini Res. Corp., 835 F.2d 279 (Fed. Cir. 1987), and the Manual of Patent Examining Procedure (“MPEP”) exclude a reference from the prior art if a subset of inventors named in the patent authored the reference and no authors of the reference are excluded. TWi responds that the Board cor- rectly applied the rule in In re Land, 368 F.2d 866 (CCPA 1966), requiring complete identity of inventive entity to ex- clude a reference from the prior art. We agree with TWi. As we explained in our Hopewell decision, “when the patented invention is the result of the work of joint inventors, the portions of the reference disclo- sure relied upon must reflect the collective work of the same inventive entity identified in the patent to be Case: 25-1463 Document: 41 Page: 9 Filed: 10/30/2025

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excluded as prior art,” slip op. at 21, and “[a]ny incongruity in the inventive entity between the inventors of a prior ref- erence and the inventors of a patent claim renders the prior disclosure ‘by another,’ regardless of whether inventors are subtracted or added to the patent,” id. at 21–22 (citing Land, 368 F.2d at 879). This is the rule applied by the Board here, see J.App’x 20, 26; that rule is not erroneous. Merck argues that the Board decision here is distin- guishable from the Board’s decision in Hopewell because the Board here did not consider the Applied Materials de- cision. See Applied Materials, 835 F.2d at 279. As we ex- plained in Hopewell, we do not read Applied Materials as deviating from the rule set forth in Land and applied by the Board here. Slip op. at 14–18. This is therefore a dis- tinction without a difference. Next, like in the Hopewell case, Merck demands a va- catur of the Board’s decision because, it says, the Adminis- trative Procedures Act (“APA”) requires the Board to provide an opportunity to submit rebuttal arguments and evidence to address the Board’s surprise adoption of its bright-line rule, in violation of the MPEP. We disagree for the reasons set forth in Hopewell. Slip op. at 22–25. Next, like in the Hopewell case, Merck argues that the Board erroneously shifted the burden of persuasion to Merck to show the named inventors’ contributions to the Bodor disclosure. Again, we disagree for the reasons set forth in Hopewell. Slip op. at 27. Relatedly, Merck argues that the Board legally erred in its corroboration analysis, erroneously requiring corrob- orated evidence of particular contributions by each inven- tor rather than applying the rule of reason in light of all the evidence. That the board here found a lack of evidence of corroboration with respect to all the inventors does not distinguish this case from Hopewell: it is enough that there is insufficient corroborated evidence of De Luca’s contribu- tion, as we affirmed in Hopewell. Id. at 25–27. Merck does Case: 25-1463 Document: 41 Page: 10 Filed: 10/30/2025

not identify any additional evidence here that would show legal (or factual) error in the Board’s analysis of De Luca’s contribution. We reject this argument for the reasons dis- cussed in Hopewell. Id. As in the Hopewell case, we need not and do not ad- dress Merck’s additional argument that the Board erred in concluding that Drs. Bodor and Dandiker were co-inven- tors of the Bodor disclosure. Id. at 27. III Merck next argues that even if Bodor is prior art, that the Board lacked substantial evidence that the combina- tion of Bodor and Rice rendered the claimed invention ob- vious. In Hopewell, this court affirmed the Board’s determi- nation that claims 36, 38, 39, and 41–46 of the ’947 patent and claims 17, 19–20, and 22–27 of the ’903 patent were unpatentable as obvious over the Bodor PTC application and the Stelmasiak reference. Id. at 28–33. Merck makes several arguments that largely parallel those made in the companion Hopewell decision. First, Merck argues that neither reference suggested the claimed retreatment period regimen after an 8–10 months no-treat- ment period because: (1) the Board’s finding that Bodor does not disclose the retreatment period for purposes of an- ticipation is internally inconsistent with its later determi- nation that Bodor suggests retreatment, compare J.App’x 34–35 with J.App’x 45; (2) Bodor’s time-limited cladribine- free period does not imply retreatment with cladribine; and (3) Rice does not disclose automatic retreatment except when certain safety criteria are met, and, even then, Rice does not disclose the particular dosing claimed regimen with 8–10 months of no treatment and a 1.7mg/kg total dose during retreatment. We disagree with each of Merck’s arguments. We see no internal inconsistency between the Board’s finding that Case: 25-1463 Document: 41 Page: 11 Filed: 10/30/2025

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Bodor does not expressly or inherently disclose retreat- ment and the Board’s finding that Bodor suggests retreat- ment. J.App’x 44–45 (citing J.App’x 2086–89 (¶¶ 109, 111– 16) (Greenberg Decl.) and J.App’x 3855 (¶ 39) (Greenberg Rebuttal Decl.)). Bodor says that practitioners should con- duct “continuous clinical evaluations . . . to determine sub- sequent therapy,” which will “aid and inform in evaluating whether to increase, reduce or continue a particular treat- ment dose.” Bodor, col. 14, ll. 43–51 (emphasis added); id. at col. 13, ll. 24–30 (noting closed-ended periods of “ten months of no treatment” or “eighteen months of no treat- ment”). Moreover, Rice expressly teaches retreatment, as Merck admits. Appellant’s Opening Br. 51 (citing Rice at J.App’x 2255) (“Rice contemplated re-treatment only when certain safety criteria were met” (emphasis in original)). That Rice discloses certain criteria prior to retreatment does not undermine Rice’s disclosure of retreatment be- cause the claims do not require that the retreatment be au- tomatic, as we explained in Hopewell. Slip op. at 30-31. The fact that Rice alone does not disclose the specific claimed dosing regimen is of no moment because it is the combination of the references that the Board held renders the claims obvious. “[O]ne cannot show non-obviousness by attacking references individually.” In re Keller, 642 F.2d 413, 426 (CCPA 1981). Substantial evidence supports the Board’s finding that the combination suggested using Bodor’s initial treatment dosage “as a logical starting point in a maintenance phase” and optimizing from there, given the express statements in Bodor that “the therapeutically effective amount of cladribine administered herein may be lowered or increased by fine[-]tuning” and that “[t]herapeu- tically effective amounts [of cladribine] may be easily de- termined, for example, empirically by starting at relatively low amounts and by step-wise increments with concurrent evaluation of beneficial effect.” J.App’x 45–46; Bodor, col. 13, ll. 31–40; J.App’x 2087–90 (¶¶ 111–18) (Greenberg Decl.). Substantial evidence supports the conclusion that Case: 25-1463 Document: 41 Page: 12 Filed: 10/30/2025

ordinary artisans could optimize the dosage for the retreat- ment phase as easily as for the initiation phase. Merck argues that, unlike in Hopewell, TWi here did not argue that lymphocyte suppression was a result-effec- tive variable, and the Board thus violated the APA by rely- ing on that reasoning in support of its obviousness determination here. See Appellant’s Opening Br. 57–58. The Board’s optimization holding was primarily based on the text of Bodor and Dr. Greenberg’s declaration, which adequately support the Board’s decision. Moreover, Dr. Greenberg expressly noted that cladribine’s “mechanism of action . . . was to induce death of lymphocytes,” J.App’x 3845 (¶ 21), which undermines Merck’s argument that TWi never raised the lymphocytes level as a basis to optimize the dosage. Finally, Merck argues that the Board erred by dis- counting “somewhat” the weight of Merck’s unexpected re- sult because Merck did not compare the results to Bodor, the closest prior art. See J.App’x 62. Merck argues that it could not compare its product to Bodor because Bodor did not include any efficacy results. We disagree. Merck does not dispute that, if Bodor is prior art, it is the closest prior art. Therefore, as the Board correctly noted, the unex- pected result analysis properly entails a comparison to Bo- dor. It is inapposite that Bodor did not include efficacy results—Merck carried the burden of production to show unexpected results. See Zup, LLC v. Nash Mfg., Inc., 896 F.3d 1365, 1373 (Fed. Cir. 2018) (“[A] patentee bears the burden of production with respect to evidence of secondary considerations of nonobviousness.”). Moreover, the Board considered Merck’s evidence of unexpected results, assign- ing it “moderate weight” that was merely “somewhat” dis- counted. J.App’x 61–62. We see no error. IV The Board’s decision here includes an unpatentability determination of claims 47 and 48 of the ’947 patent and Case: 25-1463 Document: 41 Page: 13 Filed: 10/30/2025

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claims 26 and 27 of the ’903 patent, which were not chal- lenged and thus not addressed directly in the Hopewell de- cision. Merck argues these claims together with the independent claims, and does not present any argument why we should treat these claims differently from the claims already held to be obvious. V Like in Hopewell, Merck argues that the claims here should be limited to covering weight-based dosing. We re- ject this argument for the reasons discussed in Hopewell. Slip op. at 33–34. CONCLUSION Because Bodor is prior art based on our analysis in Hopewell, and because we see no legal or factual errors in the Board’s analysis in this case, we affirm. AFFIRMED