Spectrix Therapeutics, LLC

Patent Trials and Appeals Board

Mar 14, 2022

2022000518 (P.T.A.B. Mar. 14, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 16/196,500 11/20/2018 Mark Tengler SPTH:1000CON 1083 34725 7590 03/14/2022 CHALKER FLORES, LLP 14841 NORTH DALLAS PARKWAY SUITE 575 DALLAS, TX 75254 EXAMINER AL-AWADI, DANAH J ART UNIT PAPER NUMBER 1615 MAIL DATE DELIVERY MODE 03/14/2022 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte MARK TENGLER ____________ Appeal 2022-000518 Application 16/196,500 Technology Center 1600 ____________ Before JOHN G. NEW, MICHAEL A. VALEK, and JAMIE T. WISZ, Administrative Patent Judges. VALEK, Administrative Patent Judge. DECISION ON APPEAL Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving claims to a pharmaceutical composition that have been rejected for lack of written description under 35 U.S.C. § 112(a) and for obviousness under 35 U.S.C. § 103. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies Spectrix Therapeutics, LLC and Arbor Pharmaceuticals, LLC as the real parties in interest. Appeal Br. 2. Appellant appeared for an oral hearing on February 17, 2022, and a transcript of that hearing has been made of record. Appeal 2022-000518 Application 16/196,500 2 STATEMENT OF THE CASE Appellant’s application relates to compositions for the delivery of thyroid hormones, such as levothyroxine (T4) and liothyronine (T3), for the treatment of thyroid disorders. Spec. 1. Claims 31-54 are on appeal and can be found in the Claims Appendix of the Appeal Brief. Appellant does not address the claims individually. Therefore, we select claim 31 as representative for our analysis of Examiner’s rejections. See 37 C.F.R. § 41.37(c)(1)(iv). Claim 31 reads as follows: 31. A pharmaceutical composition comprising: (i) a first portion comprising a first microparticulate comprising levothyroxine (T4) and liothyronine (T3) formulated for immediate release in a ratio of about 1:1 to about 20:1 wherein greater than 30%, 40%, 50%, 60%, 70%, or 80% by weight of the first portion of the T4 and T3 is released in a first peak within 45 minutes after the composition is introduced into an in vitro dissolution assay, wherein the conditions of the in vitro dissolution assay is a dissolution medium of 0.1 N HC1 using a USP Apparatus 2, wherein the T4 and T3 is from 0.04 weight percent (wt%) to 3.0 wt% of the first microparticulate; and (ii) a second portion comprising a second microparticulate comprising T4 and T3 formulated for extended release in a T4:T3 ratio of about 1:1 to about 20:1 resulting in a second peak after 2 hours that is greater than 10% by weight of the composition as measured in the in vitro dissolution assay, wherein the conditions of the in vitro dissolution assay are an initial dissolution medium of 0.l N HC1, and after 2 hours, the medium is adjusted to a pH of about 6.8, and the in vitro dissolution assay is performed using a USP Apparatus 2, and wherein the T4 and T3 is from 0.04 wt% to 3.0 wt% of the second microparticulate. Appeal Br. 24. The following rejections are before us: Appeal 2022-000518 Application 16/196,500 3 I. Claims 31 and 42 under 35 U.S.C. § 112(a) for failure to meet the written description requirement; II. Claims 31-38, 41-52, and 54 under 35 U.S.C. § 103 as unpatentable over Hirsh,2 Hall,3 Olon,4 Franz,5 Di Martino,6 and Moncrief;7 III. Claims 31, 36, 42, and 48 under 35 U.S.C. § 103 as unpatentable over Hirsh, Hall, Olon, Franz, Di Martino, Moncrief, and Mousa;8 and IV. Claims 31, 39, 40, 42, and 53 under 35 U.S.C. § 103 as unpatentable over Hirsh, Hall, Olon, Franz, Di Martino, Moncrief, and Krenning.9 Appeal Br. 7. I. WRITTEN DESCRIPTION REJECTION Issue The issue for this rejection is whether a preponderance of the evidence supports Examiner’s finding that claim 31 fails to comply with the written description requirement. Analysis To satisfy the written description requirement of 35 U.S.C. § 112, the inventor must “convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991) (emphasis omitted). 2 US 2005/0181050 A1, published Aug. 18, 2005 (“Hirsh”). 3 US 8,883,213 B2, issued Nov. 11, 2014 (“Hall”). 4 US 2004/0152783 A1, published Aug. 5, 2004 (“Olon”). 5 US 2003/0165564 A1, published Sept. 4, 2003 (“Franz”). 6 US 7,691,411 B2, issued Apr. 6, 2010 (“Di Martino”). 7 US 2007/0099841 A1, published May 3, 2007 (“Moncrief”). 8 US 2009/0022806 A1, published Jan. 22, 2009 (“Mousa”). 9 US 5,324,522, issued June 28, 1994 (“Krenning”). Appeal 2022-000518 Application 16/196,500 4 In this case, Examiner finds there is no written description to support the “wherein the T4 and T3 is from 0.04 weight percent (wt%) to 3.0 wt%” limitation recited for both the first and the second microparticulate of claim 31. Final Act. 2-3. Appellant contends Examiner’s prima facie showing is insufficient because “Examiner simply states that ‘the instant specification does not disclose any range of amounts of these active ingredients.’” Appeal Br. 9 (quoting Final Act. 3). In addition, Appellant argues that “the claimed weight percents are clearly taught” in its disclosure because a skilled artisan “could calculate the claimed weight percentages” from ingredient amounts set forth in the tables in the Specification. Id. at 9-10. Focusing on Table 1, Appellant explains that the low and high columns describe the low and high ends of a range for each of the listed ingredients. See id. at 10-12; Tr. 4:14- 5:8.10 According to Appellant, a microparticulate comprised of the low amount of T4 and T3 (0.013 and 0.00065 mg respectively) and the high amount of Duolite resin (33.33 mg) in Table 1 would have a T4 and T3 weight percentage at the lower end (.04%) of the recited range, whereas a particle containing the high amount of T4 and T3 (0.5 and 0.5 mg) with the high amount of resin would have a weight percentage at the higher end (3.0%) of the recited range. Appeal Br. 10-12 (showing calculations).11 10 Appellant’s interpretation of tables in the Specification is supported by the testimony of the inventor. See Declaration of Mark Tengler dated January 14, 2021 ¶ 31 (“The tables are not intended to provide two example formulations (i.e., low and high), they are to provide a range (i.e., low and high) of each ingredient to have a viable formulation that will meet all the other limitations of the requested claim structure.”). 11 Appellant acknowledges that some of the calculations in the Appeal Brief contain “typographical errors,” but contends they “do not affect the legal Appeal 2022-000518 Application 16/196,500 5 Thus, Appellant contends it “has provided examples in the specification with express support for a low and a high weight percent, which mathematically defines a range.” Reply Br. 4. We agree with Examiner’s rejection and are not persuaded by Appellant’s arguments to the contrary. As an initial matter, we determine that Examiner has presented a sufficient prima facie showing by identifying the particular limitations that are not sufficiently described, i.e., the 0.04-3 wt% range for amount of T4 and T3 in the first and second microparticulates, and explaining that there is no description of any range for the weight percentage of T4 and T3 in the Specification. Final Act. 3. Examiner further explains that the examples in the Specification’s tables “do not clearly disclose .04 wt % to 3 wt% within a first microparticulate for immediate release and a second microparticulate for extended release.” Final Act. 3. In particular, Examiner determines that Appellant’s calculations rely “on weights from different compositions - the low and high -in combination with ratios[] calculated from one specific total of carrier (33.33 mg)” and “[i]t is not clear why Appellant is calculating low amount mg of T4 and T3 with the high amount of the Duolite (33.33) carrier instead of the low amount.” Ans. 6-7.12 Thus, the ranges in the tables do not sufficiently support the recited range because “one has too much to pick and choose” between different amounts and there is nothing in the written description “that would reasonably convey to the skilled artisan that the outcome in this case because the result,” i.e., particles containing a total amount of T4 and T3 ranging from about 0.04 to 3 wt%, “is the same.” Reply Br. 2-3 (providing corrected calculations). 12 The Answer does not include page numbers. We cite to the order of pages with page 1 referring to the first page immediately following the title page. Appeal 2022-000518 Application 16/196,500 6 inventor[] considered the weight percent [range] to be part of [his] invention.” Id. at 7 (citing Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1328 (Fed. Cir. 2000) (“Purdue”)). Examiner’s reasoning is persuasive. All of the weight percent calculations Appellant presents in its briefing are premised on selecting the high amount of resin specified in Table 1.13 But Table 1 discloses that the amount of resin may range from a high amount of 33.333 mg to a low amount of 0.00065 mg. Spec. ¶ 54. If the low amount of resin and high amounts of T4 and T3 are used in the same formula that Appellant argues a skilled artisan would use to calculate the recited range, the calculated weight percent of T4 and T3 would exceed 99%.14 Thus, according to Appellant’s interpretation, Table 1 discloses a range of T4 and T3 weight percentages ranging from almost 0 to 100%. At the hearing, Appellant argued a skilled artisan would recognize that the high amounts of T4 and T3 in Table 1 could not be loaded onto the low amount of resin. See Tr. 5:4-18. However, even if we accept that one of skill in the art would recognize this edge case to be implausible, the selection of other amounts of resin within the range disclosed in Table 1 would likewise result in a weight percentage that dramatically exceeds the 13 While the Appeal Brief focuses on Table 1, we note that all of the tables in the Specification disclose the same low and high amounts for T4, T3, and the exchange resin. See Spec. ¶¶ 54-59 (Tables 1-6). 14 According to Appellant, weight percentage is calculated by dividing the amount of drug by the total amount of drug and carrier resin. Appeal Br. 10. If the high amount of T4 and T3 and low amount of resin from Table 1 are used in this formula, the resulting weight percentage of drug would be about 99.9% (i.e., 0.5+0.5/(0.5+0.5+0.00065) x 100%). Appeal 2022-000518 Application 16/196,500 7 upper 3% end of the recited range.15 Indeed, Appellant acknowledges that the range one of skill in the art could calculate from the amounts disclosed in Table 1 is “broader” than the range recited in claim 31. Tr. 8:2-10. This breadth is the central problem with Appellant’s argument that the Specification’s tables sufficiently describe the recited range. There is nothing in the written description that would lead one of ordinary skill in the art to the particular amounts that Appellant selects for the calculations in its briefing as opposed to other amounts in the same tables that can be used to calculate widely different ranges. See Gen. Hosp. Corp. v. Sienna Biopharms., Inc., 888 F.3d 1368, 1372 (Fed. Cir. 2018) (holding that, to meet the written description requirement, “where a specification discloses a broad range of values and a value within that range is claimed, the disclosure must allow one skilled in the art to ‘immediately discern the limitation at issue in the claims’” (quoting Purdue, 230 F.3d at 1323)). The only other portion of the Specification that Appellant refers to in the Appeal Brief are “the ratios taught in [0048], one in which the ratio of T4:T3 is 1:1 and another in which a ratio of T4:T3 is 20:1.” Appeal Br. 11 (citing Spec. ¶ 48). Those ratios describe the amount of T4 relative to T3. They do not describe the amount of T4 and T3 relative to the carrier used to form the microparticulates. Thus, the ratios described in paragraph 48 of the Specification do not demonstrate possession of the recited weight percentage range. 15 For example, combining the high amounts of drug with 1 mg of resin results in a T4 and T3 percentage of 50% (i.e., 0.5+0.5/(0.5+0.5+1) x 100%) or with 5 mg resin results in a T4 and T3 percentage of about 16.7% (i.e., 0.5+0.5/(0.5+0.5+5) x 100%). Appeal 2022-000518 Application 16/196,500 8 We agree with Examiner that the written description issue here is similar to that in Purdue. In Purdue, the claims recited a range requiring that the ratio of two values was greater than two. See 230 F.3d at 1323. There was no express discussion of that ratio, nor anything to suggest that ratio was important in the written description, but the patentee urged that the recited ratio was sufficiently described because it could be calculated from values reported in some of the specification’s examples. Id. at 1326. However, like Appellant’s Specification here, the written description in Purdue also disclosed examples from which a ratio less than two could be calculated and there was nothing to “indicate[] to the skilled artisan which examples embody the claimed invention and which do not.” Id. Because there was nothing to suggest that the recited ratio was “an important defining quality of the formulation” or “even [to] motivate one to calculate the ratio” from the examples, our reviewing court explained that the written description lacked the requisite “blaze marks directing the skilled artisan to the . . . ratio or what value that ratio should exceed.” Id. at 1326-27 (citing In re Ruschig, 379 F.2d 990, 994 (CCPA 1967)). Appellant’s written description suffers from a similar defect. There is no express description of the recited range, nor is there other description suggesting that the recited range is important. Accordingly, Appellant’s written description does not provide a sufficient motivation or blaze marks for a skilled artisan to calculate the recited weight percent range as opposed to weight percentages outside that range. For these reasons, that description does not sufficiently demonstrate possession of a composition comprising a first and second microparticulate each of which has a T4 and T3 weight percentage of 0.04-3%. Thus, Examiner’s rejection of claims 31 and 42 for Appeal 2022-000518 Application 16/196,500 9 lack of written description is supported by a preponderance of the evidence.16 II. OBVIOUSNESS REJECTIONS Issue All of Examiner’s obviousness rejections rely on the same combination of Hirsh, Hall, Olon, Franz, Di Martino, and Moncrief. Final Act. 4, 9, 10; see Appeal Br. 12 (noting same). In its Appeal Brief, Appellant argues the obviousness rejections collectively and does not advance any separate arguments. See Appeal Br. 12-22. Accordingly, our analysis below applies to all three rejections, focusing on claim 31 as representative. The issue for these rejections is whether the preponderance of evidence of record supports Examiner’s conclusion that the cited prior art renders claim 31 obvious. Findings of Fact FF1. Hirsh teaches “[a] multiparticulate, modified release composition for oral administration” that is “made by complexing a drug with an ion- exchange resin in the form of small particles.” Hirsh, Abstr. According to Hirsh such compositions may provide pulsatile release by including “a mixture of particles releasing a different times, for example, a formulation could contain equal amounts of immediate release particles and of enteric- coated extended release particles and thereby provide release in two pulses, 16 Appellant’s other claims incorporate the same weight percentage ranges from independent claims 31 and 42. Therefore, they likely suffer from the same written description deficiency even though they have not been rejected on this basis. Appeal 2022-000518 Application 16/196,500 10 immediate and after the drug particles reach the small intestine.” Id. ¶ 24; see also id. ¶¶ 75-78 (describing pulsatile release). FF2. Hirsh provides examples of drug-resin complexes that achieve a release of greater than 30% by weight of drug within the first 45 minutes of administration. Hirsh ¶ 116. Hirsh also provides examples of drug-resin complexes that achieve a second peak of release of greater than 10% after 2 hours. Id. ¶ 123. Hirsh notes that the data in these examples was measured by an in vitro dissolution assay in a medium of 0.1 N HCl. Id. ¶¶ 115, 123. FF3. Hirsh teaches that its compositions may comprise multiple drugs that are simultaneously administered to achieve pulsatile release of those drugs. See Hirsh ¶¶ 98-99. Hirsh lists numerous exemplary drugs for the use in such compositions, including levothyroxine, i.e., T4. Id. ¶ 35. FF4. Hirsh teaches there are a number of processes known in the art for loading a drug onto a resin to achieve a microparticulate. Hirsh ¶ 48. Hirsh further explains that “[s]everal processing methods to achieve extended release coatings on drug loaded resin particles have [also] been described” in the prior art. Id. ¶¶ 43-44, 58-62 (describing references). Some of these methods involve the use of a solvating or impregnating agent “to reduce the swelling of the drug-loaded resins and prevent the fracturing of the extended release coating.” Id. ¶ 59. In addition, Hirsh discloses an “alternative method of preparation of extended release coated drug-resin complexes without the use of impregnating agents.” Id. ¶ 58. FF5. Hirsh teaches that drug loadings of “24% or less” by weight can be achieved on a “non-swelling coated resin.” Hirsh ¶ 44. FF6. Like Hirsh, Hall teaches drug-loaded resin particle compositions to administer pharmaceutical agents such as “thyroid agents.” Hall, Abstr., Appeal 2022-000518 Application 16/196,500 11 10:35-38. Hall explains that “[t]he drug may be loaded in a specific concentration to allow the specific release of the drug over a given time range” and that a concentration of bound drug “between about 1% and about 50%” is contemplated by the use of various techniques to control swelling of the resin. Id. at 9:40-45; see also id. at 6:48-66 (discussing control of swelling). Hall also teaches that “two or more pharmaceutical compositions” may be loaded onto the resin to achieve various release profiles. Id. at 26:21-34. FF7. Olon teaches the administration of admixtures of “L-thyroxine (T4) and liothyronine (T3)” to produce state serum levels of T3. Olon, Abstr. Olon teaches that a favorable serum level of T3 can be achieved when T4 and T3 are administered together at “higher ratios of T4 to T3 (approximately greater than 4:1).” Id. ¶ 24. Olon further teaches that such combinations of T4 and T3 may be administered in a “pulse release” dosage form. Id. ¶ 38. FF8. Franz teaches pharmaceutical compositions of T4 and T3. Franz, Abstr. Franz teaches that the amount of these active ingredients “can vary widely, as desired” and is preferably in “the range of about 0.001 to 5 weight %.” Id. ¶¶ 73-75. FF9. Di Martino discloses pharmaceutical formulations of T4 and T3 for oral administration. Di Martino, Abstr. Di Martino teaches that these formulations contain T4 and T3 in a concentration of 0.001-1% by weight. Id. at claim 16. FF10. Moncrief discloses amino acid and peptide conjugates comprising T4 and T3 for the treatment of thyroid disorders. Moncrief, Abstr. Moncrief teaches that “[o]ne of ordinary skill in the art would recognize a variety of structures, such as bead constructions and coatings, useful for achieving Appeal 2022-000518 Application 16/196,500 12 particular release profiles,” including pulse release and combinations of various other release profiles. Id. ¶ 153. Analysis Examiner finds Hirsh teaches pharmaceutical compositions comprising combinations of drugs complexed on ion-exchange resin particles to form immediate and extended release microparticulates (i.e., a first and second microparticulate) that achieve pulsatile release with a first pulse within about one hour of ingestion and a second pulse after two hours as recited in claim 31. Final Act. 5-6. Examiner further determines that Hirsh discloses the particles may be loaded with lower amounts of drug, i.e., 24% by weight or less, which overlaps with the recited weight percentage range. Final Act. 6; Ans. 17-19. Examiner also finds that Hall teaches an overlapping range of drug, i.e., 1-50 wt%, in a similar drug-loaded resin composition. Ans. 17. Examiner acknowledges that Hirsh does not disclose the combination of T4 and T3 specifically, but points out that Hirsh teaches its formulations may be used with a variety of drugs, including T4. Examiner relies on the other references, e.g., Olon and Franz, which teach the combination of T4 and T3 in an oral dosage form, and Olon’s teaching of a ratio of T4 to T3 that overlaps with the ratio recited in claim 31. Final Act. 7-8. Based on these teachings, Examiner determines it would have been obvious this combination of T4 and T3 in Hirsh’s drug-loaded resin, microparticulate composition to achieve the release profile recited in claim 31. Final Act. 7-9; see also Ans. 18-19 (explaining that the difference between Hirsh and Appellant’s claims is the use of “the T3 and T4 thyroid hormones together” and that the other references “would have led one of ordinary skill in the art to modify and combine prior art teachings to arrive at Appeal 2022-000518 Application 16/196,500 13 the claimed invention, namely using T3 and T4 in the amounts recited”). After considering the full record, we agree with and adopt Examiner’s findings of fact and conclusion of obviousness as articulated in the Final Action and Answer (Final Act. 4-12; Ans. 7-26; FF1-10). As explained below, we are not persuaded by the arguments advanced in the Appeal Brief. Appellant argues that Hirsh teaches “volume filling the resin particles under high temperature prior to coating” to avoid the coating swelling and breaking upon exposure to water. Appeal Br. 14. According to Appellant, a skilled artisan would recognize that heating T4 and T3 as taught in Hirsh would cause them to “degrade at different rates” and thus “when reading Hirsh as a whole, would not use the Hirsh methodology, viz., high- temperature treatment loading of active agent onto a resin” with such agents. Id. (quoting Declaration of Mark Tengler dated October 25, 2019 ¶ 15). Appellant’s argument is not persuasive because it erroneously assumes that Hirsh’s teachings require the active agent to be loaded onto the resin at high temperature. In fact, Hirsh teaches there are a variety of known methodologies for producing a drug-loaded resin microparticulate. FF4. Examiner points out that at least some of these methods involve loading the drug at room temperature. Ans. 8. The premise for Appellant’s argument that Hirsh requires high temperature loading appears to be Hirsh’s teachings regarding another reference, Kelleher (US 4,996,047). See Appeal Br. 14-15; Reply Br. 6. According to Hirsh, Kelleher found “the degree of drug loading required to prevent swelling and rupture of extended release coatings when loaded resins are placed in aqueous solutions, in the absence of fillers or impregnating agents . . . was at least 38%” by weight. Hirsh ¶ 43. Hirsh Appeal 2022-000518 Application 16/196,500 14 discloses an alternative method whereby resin particles can be loaded with a lower amount of drug without the need for a filler or impregnating agent. FF4. In Hirsh’s examples, this loading occurs at 90°C, i.e., what Appellant refers to as “high-temperature treatment loading.” Appeal Br. 14. The flaw with Appellant’s argument is that Hirsh’s teachings are not limited to its examples. See Hirsh ¶ 105 (referring to the examples as “non- limiting”). As noted above, Hirsh teaches and cites references describing other drug-loading methods that do not require high temperatures. Moreover, Hirsh teaches that the problem with the coating swelling and rupturing on microparticulates with lower drug concentrations can be avoided by using a filler or impregnating agent in the loading process. FF4. While it is true that Hirsh teaches an alternative technique that avoids the use of such an agent, “all disclosures of the prior art, including unpreferred embodiments, must be considered.” Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (quoting In re Lamberti, 545 F.2d 747, 750 (CCPA 1976)). Thus, the fact that Hirsh’s authors express a preference for their technique over other methods involving the use of an impregnating agent does not avoid a finding that it also would have been obvious to use any of these methods to produce microparticulates. See Merck, 874 F.2d at 807. Nor does claim 31 exclude the use of an impregnating agent to produce non-swelling microparticulates having a lower concentration of drug as taught in Hirsh. See FF4. Appellant’s reliance on the testing described in the declaration of its inventor is unavailing for similar reasons. Appeal Br. 16-18 (citing Declaration of Mark Tengler dated January 14, 2021 (“Tengler Decl.”)). According to Appellant, the testing described in the Tengler Declaration Appeal 2022-000518 Application 16/196,500 15 shows that “Hirsh does not operate when an active agent is loaded following its teaching to 15 wt%” because the coating “ruptured . . . when introduced to an aqueous environment.” Id. at 17. Thus, Appellant argues that Examiner’s finding Hirsh teaches microparticulates having an even lower weight percentage of drug, as recited in claim 31, “is clear error.” Id. We disagree. The testing in the Tengler Declaration was conducted on microparticulates prepared according to the method in Hirsh’s examples. See Tengler Decl. ¶¶ 14-16; Tengler Decl. Ex. A. But as explained above, Hirsh’s teachings are not limited to its examples. In particular, Hirsh evidences that a skilled artisan would be aware of other methods for preparing drug-loaded resin particles involving the use of an impregnating agent to avoid swelling of the coating when lower concentrations of drug are used. FF4. Thus, even accepting Appellant’s position that the method employed in Hirsh’s examples does not avoid swelling when lower amounts of drug are loaded, the Tengler Declaration does not suggest that the other loading techniques Hirsh describes, e.g., those involving the use of an impregnating agent to avoid swelling, are inoperable. Finally, Appellant argues that Examiner relies on impermissible hindsight to combine the references. Appeal Br. 19-22. Again, we disagree. Examiner has articulated a sufficient rationale for employing the combination of T4 and T3 at a ratio within the recited range, as taught in Olon and Franz (FF7, FF8), in a drug-loaded resin formulation comprising different types of microparticulates to achieve pulsatile release, as taught in Hirsh and Hall (FF1-FF6). See Final Act. at 7-9; see also Ans. 18-19. Examiner has also established that a skilled artisan would have had a reasonable expectation of achieving particles having a weight percentage of Appeal 2022-000518 Application 16/196,500 16 T4 and T3 within the recited range because both Hirsh and Hall teach particles having overlapping weight percentage ranges. FF5, FF6. Appellant’s argument that the cited art “fails to teach how to overcome [Hirsh’s] problem with lowering the weight percent of the active on the resin particles . . . to prevent breakage of the coating” (see Appeal Br. 19-21) is unavailing for the reasons explained above. Appellant’s remaining attempts to distinguish Hall, Olon, Franz, Di Martino, and Moncrief based on the differences between claim 31 and each of those references individually (see Appeal Br. 19-21) are similarly unavailing because “[n]on- obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references.” Soft Gel Techs., Inc. v. Jarrow Formulas, Inc., 864 F.3d 1334, 1341 (Fed. Cir. 2017) (quoting In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986)). For these reasons, each of Examiner’s rejections of claim 31 as obvious are supported by a preponderance of the evidence. We therefore affirm. The obviousness rejections of Appellant’s other claims, which are not argued separately from claim 31, are affirmed for the same reasons. CONCLUSION In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 31, 42 112(a) Written Description 31, 42 31-38, 41- 52, 54 103 Hirsh, Hall, Olon, Franz, Di Martino, Moncrief 31-38, 41- 52, 54 31, 36, 42, 48 103 Hirsh, Hall, Olon, Franz, Di Martino, Moncrief, Mousa 31, 36, 42, 48 Appeal 2022-000518 Application 16/196,500 17 Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 31, 39, 40, 42, 53 103 Hirsh, Hall, Olon, Franz, Di Martino, Moncrief, Krenning 31, 39, 40, 42, 53 Overall Outcome 31-54 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED