SANDOZ AG

Patent Trials and Appeals BoardMay 26, 2021

2020005251 (P.T.A.B. May. 26, 2021)

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. 14/905,990 01/19/2016 Rok Staric 71603.US 1028 408 7590 05/26/2021 LUEDEKA NEELY GROUP, P.C. P O BOX 1871 KNOXVILLE, TN 37901 EXAMINER THAKOR, DEVANG K ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 05/26/2021 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): LNG.PATENT@gmail.com docketing@luedeka.com eofficeaction@appcoll.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte ROK STARIC, SANDRA BERGLEZ, JERNEJ GRMAS, TIJANA STANIC LJUBIN, ROK GRAHEK, and LUKA PETERNEL1 ____________ Appeal 2020-005251 Application 14/905,990 Technology Center 1600 ____________ Before RICHARD M. LEBOVITZ, JOHN G. NEW, and ROBERT A. POLLOCK, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies Sandoz AG as the real party-in- interest. App. Br. 2. Appeal 2020-005251 Application 14/905,990 2 SUMMARY Appellant files this appeal under 35 U.S.C. § 134(a) from the Examiner’s Non-Final Rejection of claims 1–4, 15–20, and 22. Specifically, claims 1–4, 15, 16, 19, and 20 stand rejected as unpatentable under 35 U.S.C. § 103 as being obvious over the combination of Fort et al. (US 2007/0249692 A1, October 25, 2007) (“Fort”) and Puskas et al. (WO 2012/163546 A1, December 6, 2012) (“Puskas”).2 Claims 17 stands rejected as unpatentable under 35 U.S.C. § 103 as being obvious over the combination of Fort, Puskas, and Leplatois et al. (US 2010/0170820 A1, July 8, 2010) (“Leplatois”). Claims 18 stands rejected as unpatentable under 35 U.S.C. § 103 as being obvious over the combination of Fort, Puskas, and Farshi et al. (WO 2012/004691 A2, January 12, 2012) (“Farshi”). Claims 22 stands rejected as unpatentable under 35 U.S.C. § 103 as being obvious over the combination of Fort, Puskas, and Chow et al. (US 2008/0132560 A1, June 5, 2008) (“Chow”). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellant’s claimed invention is directed to an amorphous solid dispersion comprising at least one polymer and dapagliflozin. Abstr. 2 The Examiner notes that the citations to Puskas are drawn from Puskas et al. (US 2014/0249098 A1, September 4, 2014), which is of record. We adopt the same practice herein. Appeal 2020-005251 Application 14/905,990 3 REPRESENTATIVE CLAIM Independent claim 1 is representative of the claims on appeal and recites: Claim 1. Amorphous solid dispersion of at least one suitable polymer and dapagliflozin ((2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3- (4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H- pyran-3,4,5-triol) of formula 1 formula 1. wherein the at least one polymer is selected from the group consisting of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylic acid (PAA), poly( ethylene glycol) (PEG), poly(ethylene oxide) (PEO), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), copovidone, hypromellose acetate succinate (AQOAT), polyacrylates, and mixtures thereof, and wherein the dapagliflozin is not present in the form of inclusion complexes with the polymer and wherein the dispersion does not comprise cyclodextrin or a cyclodextrin derivative. App. Br. 13. ISSUES AND ANALYSIS We agree with, or adopt, the Examiner’s findings, reasoning, and conclusion that the claims are obvious over the combined cited prior art. We address below the arguments raised by Appellant. Appeal 2020-005251 Application 14/905,990 4 Issue Appellant argues that the Examiner erred because the combined cited prior art neither teaches nor suggests the limitations of claim 1 requiring: (1) the lack of inclusion complexes and (2) the lack of cyclodextrin or a cyclodextrin derivative. App. Br. 10. Analysis The Examiner finds that Fort teaches an amorphous solid dispersion of at least one polymer and a drug, in which the polymer is PEG and/or PVP. Final Act. 4 (citing Fort ¶¶ 2, 23, claim 7). The Examiner finds that Fort teaches that its composition is useful for maintaining the amorphous state of the drug by preventing crystallization of the drug. Id. (citing Fort Abstr., ¶ 43). The Examiner finds that Puskas teaches that it is preferable for dapagliflozin to be delivered in amorphous form. Final Act. 4 (citing Fort ¶ 54). The Examiner concludes that it would have been obvious to a person of ordinary skill in the art to use the amorphous solid dispersion of Fort to deliver dapagliflozin. Final Act. 4. The Examiner reasons that, because Fort teaches that its composition is a solid dispersion, the dapagliflozin would not be present in the form of inclusion complexes with the polymer. Id. Appellant argues that, although Fort describes, in generic terms, the inclusion of polymers such as PEG, PVP, or HPMC into a solid dispersion pharmaceutical formulation, Fort is silent with respect to the application of this composition specifically to dapagliflozin or to other antidiabetic medicines. App.Br. 9–10. Rather, Appellant contends, Fort teaches solid Appeal 2020-005251 Application 14/905,990 5 dispersions related to HIV protease inhibitors. Id. at 10. According to Appellant, Fort neither teaches nor suggests using any anti-diabetic agent and provides no motivation to a skilled artisan to prepare a dapagliflozin formulation such as that recited in Claim 1. Id. Appellant next points to the Examiner’s reliance upon Puskas as teaching formulations containing dapagliflozin. App. Br. 10. Appellant argues that the teachings of Puskas contradict at least two of the limitations of claim 1, specifically: (1) the lack of inclusion complexes and (2) the lack of cyclodextrin or a cyclodextrin derivative. Id. According to Appellant, Puskas is specifically directed to pharmaceutical compositions, including dapagliflozin, in the form of a dapagliflozin-cyclodextrin inclusion complex. Id. (citing, e.g., Puskas Abstr., ¶¶ 13–26, claims 1, 2). Appellant asserts that the central point of Puskas’ teachings is dapagliflozin in the form of inclusion bodies together with cyclodextrin. Id. Specifically, argues Appellant, Puskas fails to teach or suggest any dapagliflozin composition that does not also include cyclodextrin inclusion complexes. Id. Furthermore, argues Appellant, the “Background of the Invention” section of Puskas (i.e., ¶¶ 1–12) describes various other dapagliflozin compositions as being unsatisfactory. App. Br. 10. Therefore, Appellant contends, to a person of ordinary skill in the art, Puskas implies that dapagliflozin should be formulated together with cyclodextrin as inclusion complexes. Id. Furthermore, Appellant argues, because this is the only teaching in the cited references directed specifically to dapagliflozin, a skilled artisan, understanding the teachings of the reference, would have followed this specific teaching, and would not have arrived at the present invention, which specifically excludes inclusion bodies. Id. Appellant Appeal 2020-005251 Application 14/905,990 6 asserts that this teaching cannot be separated from the remainder of the Puskas reference relating to amorphous forms. Id. (citing In re Wesslau, 353 F.2d 238, 241 (C.C.P.A. 1965). Furthermore, Appellant argues, claim 1 expressly states that that the dispersion does not comprise cyclodextrin or a cyclodextrin derivative. App. Br. 11. Appellant asserts that this is contrary to the teaching of Puskas, which is to formulate dapagliflozin together with cyclodextrin. Id. (citing, e.g., Puskas Abstr., ¶ 13 (teaching that the “objects of the present invention can be solved by pharmaceutical compositions comprising dapagliflozin and cyclodextrin”), ¶ 17 (teaching that “the present invention can be directed to a process for producing a pharmaceutical composition comprising dapagliflozin and cyclodextrin”)). Therefore, argues Appellant, the limitation of claim 1 requiring that the dispersion does not comprise cyclodextrin or a cyclodextrin derivative is not taught or suggested by the cited prior art. Id. Appellant also asserts that no teaching or suggestion by Fort contradicts the use of cyclodextrin, as taught by Puskas. App. Br. 11. Appellant points out that Fort expressly teaches that, in addition to the excipients listed in paragraph [0023], Fort teaches that the final pharmaceutical composition may also include a variety of other pharmaceutically acceptable carriers, diluents, or excipient. Id. (citing Fort ¶¶ 24, 49). The Examiner responds Fort is not directed exclusively to HIV protease inhibitors, but expressly teaches that “it would be a significant contribution to the art to provide a stable solid dispersion pharmaceutical formulation which demonstrates a lack of crystallization,” and that the Appeal 2020-005251 Application 14/905,990 7 disclosed invention “provides novel solid dispersion pharmaceutical formulations which demonstrate an inhibition of crystallization.” Ans. 4 (quoting Fort ¶¶ 22, 23). Specifically, the Examiner finds that Fort teaches that its “invention provides a stable solid dispersion pharmaceutical formulation comprising a pharmaceutical compound, a water soluble carrier, such as polyethylene glycol (PEG), and a crystallization inhibitor, such as polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC).” Id. (quoting Fort ¶ 23). The Examiner specifically points to Fort’s teaching that: [T]his invention pertains to the preparation of solid dispersion systems for pharmaceuticals which demonstrate a lack of crystallization. The invention involves dispersion in a hydrophilic matrix of pharmaceuticals which exhibit poor aqueous solubility. The intent of such a formulation is to improve the aqueous dissolution properties and ultimately achieve improved bioavailability. Typically, the intent of such systems is to generate a dispersion of amorphous (high energy) drug within the matrix. The presence of the high energy drug form usually improves the dissolution rate. However, these systems are not often physically stable. The drug can crystallize over time, causing the loss of the desired properties and reduced shelf-life. The current invention enhances the physical stability of such formulations, thereby making this type of formulation more feasible. Ans. 4 (quoting Fort ¶¶ 42, 43). The Examiner finds that nothing about this teaching is specific to, or requires, HIV protease inhibitors. Id. at 5. With respect to Appellant’s argument that Puskas requires the formulation of dapagliflozin together with cyclodextrin, the Examiner responds that the rejection relies upon Puskas solely as teaching the Appeal 2020-005251 Application 14/905,990 8 properties of the drug, dapagliflozin, for which the formulation of Fort would be expected to be beneficial. Ans. 8. The Examiner notes that the rejection does not rely on any other aspects of Puskas, or any teaching of Puskas with respect to formulation. Id. Specifically, the Examiner relies upon Puskas as teaching that it is preferable for dapagliflozin to be delivered in amorphous form. Ans. 8. The Examiner reasons that, given that Fort teaches a drug formulation used to maintain drugs in their amorphous state, the combination of Puskas and Fort would have provided motivation to a skilled artisan to use the formulation for drugs to be delivered in amorphous form. Id. The Examiner acknowledges that Puskas is relied on solely as teaching dapagliflozin, and for its teaching that it should be delivered in amorphous form, and no other claim limitations. Ans. 9. The Examiner concludes that this teaching, combined with Fort’s teaching of a drug formulation that maintains the amorphous form, renders obvious the use of Fort’s formulation for delivering dapagliflozin. Id. The Examiner declares that it is irrelevant whether the formulations taught by Puskas contain inclusion complexes and cyclodextrin, because, reading Fort in light of Puskas, one of ordinary skill would not have relied on formulation aspects of Puskas in choosing a drug for the formulation of Fort. Id. The Examiner maintains that the formulation of Fort, taught to maintain the amorphous state of drugs through its own addition of a crystallization inhibitor to the solid dispersion, would have been reasonably expected to maintain the amorphous state of dapagliflozin without requiring additional formulations taught by Puskas. Id. This is so, the Examiner reasons, because Fort teaches Appeal 2020-005251 Application 14/905,990 9 that adding a crystallization inhibitor to a solid dispersion maintains the amorphous state of drugs, with requiring other components. Id. The Examiner responds further, with respect to Appellant’s argument that Puskas does not disclose a dapagliflozin composition that does not also include cyclodextrin inclusion complexes, and that Puskas teaches that other dapagliflozin formulations are unsatisfactory. The Examiner reasons that it is not necessary for Puskas to disclose dapagliflozin compositions that do not also include cyclodextrin inclusion complexes, because Puskas is not relied upon as teaching the dapagliflozin/cyclodextrin formulation. Ans. 10. The Examiner finds that Fort teaches a formulation that would have been reasonably expected by a skilled artisan to be beneficial for delivering dapagliflozin, because it keeps the drug in its amorphous state (without requiring cyclodextrin inclusion complexes). Id. The Examiner also finds that Puskas teaches that dapagliflozin is a drug that should be delivered in an amorphous state. Id. Furthermore, the Examiner finds, Appellant’s argument ignores the reason why the previous formulations were unsatisfactory. Id. The Examiner finds Puskas teaches that the reason why prior dapagliflozin formulations were unsatisfactory was that the dapagliflozin was micronized and that it was crystalline form. Id. (citing Puskas ¶ 8). We are not persuaded by Appellant’s arguments that the Examiner erred in finding the claimed subject matter obvious. Fort is directed to “a stable solid dispersion pharmaceutical formulation comprising a pharmaceutical compound, a water soluble carrier, such as polyethylene glycol (PEG), and a crystallization inhibitor, such as polyvinylpyrrolidone Appeal 2020-005251 Application 14/905,990 10 (PVP) or hydroxypropylmethylcellulose (HPMC).” Fort ¶ 23. In describing the state of the contemporaneous art, Fort teaches that: One measure of the potential usefulness of an oral dosage form of a pharmaceutical agent is the bioavailability observed after oral administration of the dosage form. Various factors can affect the bioavailability of a drug when administered orally.… Aqueous solubility is one of the most important of these factors. When a drug has poor aqueous solubility, attempts are often made to identify salts or other derivatives of the drug which have improved aqueous solubility. Id. at ¶ 3. Specifically, Fort teaches: For a variety of reasons, including patient compliance and taste masking, a solid dosage form, such as a capsule or tablet, is usually preferred over a liquid dosage form. However, oral solid dosage forms of a drug generally provide a lower bioavailability than oral solutions of the drug. …. An alternative dosage form is a solid dispersion. The term solid dispersion refers to the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (or fusion), solvent, or melting-solvent methods. Id. at ¶¶ 4–5. Referring to its own invention, Fort teaches: The invention involves dispersion in a hydrophilic matrix of pharmaceuticals which exhibit poor aqueous solubility. The intent of such a formulation is to improve the aqueous dissolution properties and ultimately achieve improved bioavailability. Typically, the intent of such systems is to generate a dispersion of amorphous (high energy) drug within the matrix. The presence of the high energy drug form usually improves the dissolution rate. However, these systems are not often physically stable. The drug can crystallize over time, causing the loss of the desired properties and reduced shelf-life. The current invention enhances the physical stability of such formulations, thereby making this type of formulation more feasible. Appeal 2020-005251 Application 14/905,990 11 Id. at ¶ 43. We note here that, contrary to Appellant’s argument, the teachings of Fort are not restricted to antiretroviral protease inhibitors, but more generally relate to “pharmaceuticals which exhibit poor aqueous solubility” and which may be prone to crystallization. Id. Puskas teaches that “dapagliflozin when provided in crystalline form is hygroscopic. Thus, it tends to attract water molecules from the surrounding environment through absorption, which leads to diffluence of the active substance, thereby impairing processing abilities and storage stability.” Puskas ¶ 8. Puskas teaches, of its invention, that: In particular, dapagliflozin should be provided in a form having superior solubility and processing abilities. Preferably, dapagliflozin should be provided in a form, which is highly soluble. In addition, dapagliflozin should be provided in a form, which allows oral application independently from meals. The increase in solubility and permeability should particularly be achieved without a micronization step and preferably without the use of excipients or co-solvents. Moreover, dapagliflozin should be provided in a non-hygroscopic form. Id. at ¶ 10. Puskas also teaches that “it was an object of the invention to provide dapagliflozin in a form having superior storage properties. Preferably, storage stability for 12 months at 40° C. and 75% humidity should be achieved.” Id. at ¶ 11. Puskas’ teaches a solution to achieving this desired: The objects of the present invention can be solved by pharmaceutical compositions comprising dapagliflozin and cyclodextrin, preferably as dapagliflozin cyclodextrin inclusion complex, more preferably as “genuine” dapagliflozin- cyclodextrin inclusion complexes and a method for forming such pharmaceutical compositions. Preferably, said preferred inclusion complex can be regarded as a supramolecular, noncovalent inclusion complex. Appeal 2020-005251 Application 14/905,990 12 …. A subject of the present invention thus can be a pharmaceutical composition comprising dapagliflozin and cyclodextrin, preferably as an inclusion complex. Puskas ¶¶ 13–14. Puskas teaches that an advantageous composition for pharmaceutical compositions with dapagliflozin as the active agent can comprise “dapagliflozin and cyclodextrin, preferably as dapagliflozin cyclodextrin inclusion complex.” Puskas ¶ 13. However, a person of ordinary skill in the art, familiar with the teachings of Fort, would understand that dapagliflozin could also be incorporated into a solid dispersion with a crystallization inhibitor (e.g., PVP) to prevent crystallization of the dapagliflozin and extend its shelf life, an end that is expressly taught by both Puskas and Fort as being desirable. See Fort ¶ 4; Puskas ¶¶ 10–11. We agree with the Examiner’s reasoning that it would have been obvious to combine the references, because Fort teaches a composition generally useful to maintain the amorphous state of drugs, and because Puskas teaches that dapagliflozin is a drug for which the amorphous state is preferred. Put in other words, both Puskas and Fort teach compositions capable of acting as vehicles for the active agent dapagliflozin, both of which are capable of providing better bioavailability and storage properties. As such, we conclude that it would have been obvious for a person skilled in the art to combine the active agent dapagliflozin with the solid dispersion composition of Fort. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (holding that “the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results”); see also id. at 421 (“Where a skilled artisan merely pursues ‘known options’ from a ‘finite Appeal 2020-005251 Application 14/905,990 13 number of identified, predictable solutions,’ obviousness under § 103 arises”. Appellant argues that, because Puskas teaches dapagliflozin- cyclodextrin inclusion complexes, and claim 1 expressly precludes inclusion complexes, a person of ordinary skill in the art would not have found it obvious to combine the teachings of Puskas with those of Fort. See App. Br. 10. However, Puskas teaches “pharmaceutical compositions comprising dapagliflozin and cyclodextrin, preferably as dapagliflozin cyclodextrin inclusion complex, more preferably as “genuine” dapagliflozin-cyclodextrin inclusion complexes.” Puskas ¶ 13. Consequently, a person of ordinary skill in the art would understand that Puskas contemplates pharmaceutical compositions comprising dapagliflozin and cyclodextrin without inclusion complexes, and therefore inclusion complexes, while preferred, are not necessary. See Merck & Co., Inc. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that “‘all disclosures of the prior art, including unpreferred embodiments, must be considered’” (quoting In re Lamberti, 545 F.2d 747, 750 (C.C.P.A. 1976). We agree with Appellant that Puskas teaches only compositions comprising dapagliflozin with cyclodextrin. However, and as we have explained, Puskas teaches that the combination of dapagliflozin and cyclodextrin is advantageous because it provides a combination that provides a form having superior solubility and processing abilities, allows oral application independently, is in a non-hygroscopic form, and is in a form having superior storage properties. Puskas ¶¶ 10, 11. Fort similarly teaches a carrier composition that address these issues. Fort teaches a solid amorphous solid dispersion with increased solubility and bioavailability, Appeal 2020-005251 Application 14/905,990 14 provides improved oral bioavailability, stabilizes the amorphous volume of the polymer matrix and hinders dissolution of the drug, and improves stability of the stored drug. See Fort ¶¶ 48, 50, 45, 33, Fig. 7). To summarize, both Fort and Puskas teach what are essentially carrier compositions that each address some of the issues posed in the employment of dapagliflozin as an active agent in a pharmaceutical carrier. As such, we conclude, for the reasons that we explained, to combine the teachings of Fort and Puskas, exchanging one carrier for another, to provide the predictable result of increased bioavailability and extended storage of dapagliflozin in a pharmaceutical composition. See KSR, 550 U.S. at 416. Appellant does not argue the rejections of claims 17, 18, and 22 separately. We consequently affirm the Examiner’s rejection of the independent and dependent claims together, for the reasons we have set forth supra. CONCLUSION The rejection of claims 1–4, 15–20, and 22 as unpatentable under 35 U.S.C. § 103 is affirmed. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R. § 1.136(a)(1)(iv). Appeal 2020-005251 Application 14/905,990 15 AFFIRMED Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–4, 15, 16, 19, 20 103 Fort, Puskas 1–4, 15, 16, 19, 20 17 103 Fort, Puskas, Leplatois 17 18 Fort, Puskas, Farshi 18 22 Fort, Puskas, Chow 22 Overall Outcome 1–4, 15–20, 22