PATHEON SOFTGELS INCDownload PDFPatent Trials and Appeals BoardMay 24, 20212020005453 (P.T.A.B. May. 24, 2021) Copy Citation 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. 16/012,961 06/20/2018 Nachiappan Chidambaram 215336-9003-US07 6347 149398 7590 05/24/2021 Michael Best & Friedrich LLP (Patheon) 790 N WATER ST SUITE 2500 MILWAUKEE, WI 53202 EXAMINER VU, JAKE MINH ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 05/24/2021 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): beth.obrien@thermofisher.com mkeipdocket@michaelbest.com pair_thermofisher@firsttofile.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte NACHIAPPAN CHIDAMBARAM and AQEEL A. FATMI Appeal 2020-005453 Application 16/012,961 Technology Center 1600 Before JOHN G. NEW, TAWEN CHANG, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims to a liquid dosage form of sodium naproxen as being obvious. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 We use the term “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as Patheon Softgels Inc., which is wholly owned by Thermo Fisher Scientific Inc. (Appeal Br. 3.) Appeal 2020-005453 Application 16/012,961 2 STATEMENT OF THE CASE Soft gelatin capsules (softgels) are used to encapsulate vitamins and pharmaceuticals in a liquid vehicle or carrier. (Spec. 1.) However, “[n]ot all liquids may be enclosed in softgels.” (Id.) For example, “[h]ighly acidic liquids may hydrolyze the gelatin, resulting in leaks, while basic liquids may tan the gelatin, resulting in decreased solubility of the gelatin shell.” (Id.) Moreover, “solvents such as propylene glycol, glycerin, low molecular weight alcohols, ketones, acids, amines, and esters all tend to degrade or dissolve the gelatin shell to some extent.” (Id.) And, “water tends to dissolve the gelatin shell” so “[l]iquids containing more than about 20% water by weight are generally not enclosed in soft gels.” (Id.) “Suitable softgel solutions . . . must . . . have sufficient solvating power to dissolve a large amount of the pharmaceutical agent to produce a concentrated solution” but include solvent volumes small enough to produce a softgel capsule that is a size that can be taken by patients, and do “not dissolve, hydrolyze or tan the gelatin shell.” (Id. at 2.) Appellant’s invention is directed to liquid dosage forms of sodium naproxen for softgels. (Id.) Claims 1–10 and 13–22 are on appeal. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A soft gelatin capsule comprising a fill material comprising: (a) a naproxen salt; (b) a deionizing agent comprising acetic acid, propionic acid, pyruvic acid, or lactic acid in an amount of from 0.2 to 1.0 mole equivalents per mole of naproxen salt; (c) polyethylene glycol; and (d) one or more solubilizers. (Appeal Br. 24.) Appeal 2020-005453 Application 16/012,961 3 REFERENCES The prior art relied upon by the Examiner is: Name Reference Date Yu et al. US 5,360,615 Nov. 1, 1994 Ulloa et al. US 2003/0216423 A1 Nov. 20, 2003 Popp US 2005/0158377 A1 July 21, 2005 Tanner et al. US 2006/0099246 A1 May 11, 2006 REJECTION The following rejection by the Examiner is before us for review: Claims 1–10 and 13–22 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Yu, Tanner, Popp, and Ulloa. DISCUSSION The Examiner finds that Yu teaches enhancing the solubility of pharmaceuticals for encapsulation in soft capsules where the pharmaceutical composition includes “a basic pharmaceutical agent,” “0.2–1.0 mole equivalent of hydrogen species . . . such as fumaric or citric acid,” polyethylene glycol, and “solubilizers, such as propylene glycol and polyvinylpyrrolidone.” (Non-Final Action 3, 4.) According to the Examiner, “YU does not teach using a specific basic pharmaceutical drug, such as naproxen sodium; or using a specific organic acid, such as lactic acid.” (Id. at 3.) However, the Examiner finds that doing so would have been obvious from the teachings of Tanner, Popp, and Ulloa. (Id. at 4–5.) The Examiner finds that Tanner teaches encapsulated liquid medications in soft gels like Yu, and that “the prior art had known naproxen sodium salt (see [0067]), which is alkaline and would be a basic drug (see abstract), wherein naproxen sodium is typically administered in place of naproxen, which is an acidic drug (see [0067]).” (Id. at 4.) The Examiner Appeal 2020-005453 Application 16/012,961 4 further finds that Tanner teaches “[t]he typical formulation for naproxen sodium is disclosed with water and polyethylene glycol in Table XIV (see [0068]).” (Id.) The Examiner relies on Popp as teaching that fumaric and lactic acid were known organic acids that “are functional equivalents,” and Ulloa for the teaching that naproxen was known in the art to treat pain. (Id. at 4–5.) The Examiner concludes that, in view of the foregoing references, it would have been obvious to one having ordinary skill in the art to include “naproxen sodium as the basic pharmaceutical in YU’s composition” as well as use lactic acid, instead of fumaric acid, and include a solubilizer “as taught by YU.” (Id. at 4.) According to the Examiner, one would have been motivated to do so “because it would enhance the solubility of the naproxen sodium salt to further prevent precipitation or allow a higher drug dosage if needed.” (Id.) We do not agree with the Examiner’s conclusion of obviousness for the reasons that follow. Yu teaches that naproxen is an acidic pharmaceutical agent, and that “the present solvent system enhances the solubility of acidic pharmaceutical agents in polyethylene glycol by increasing the number of species of the acidic agent (ionized and unionized) that are available to go into solution and by providing adequate solvation for each species.” (7:1–6.) Yu teaches that polyethylene glycol has both hydrophobic and hydrophilic binding sites and that solubility of acidic pharmaceutical agents is increased when nonionized species are present as well as ionized species because both binding sites of polyethylene glycol are used. (Id. at 7:6–10.) Thus, hydroxide ion is added to the free acid agent to ensure deprotonation of the Appeal 2020-005453 Application 16/012,961 5 acidic drug such that an ionized species of naproxen (i.e., the free acid) is present along with a nonionized species (i.e., the deprotonated free acid) to take full advantage of the hydrophobic and hydrophilic binding sites of the polyethylene glycol. (Id. at 7:16–26.) The Declaration of Dr. Kaspar van den Dries2 supports the foregoing. (Van den Dries Declaration ¶¶ 12, 14.) It is true that Yu teaches a similar concept for basic pharmaceutical agents. (Id. at 9:35–46; Van den Dries Declaration ¶ 17.) However, Yu refers not to salts of pharmaceutical agents that are basic agents, but to an agent that is basic in its ionized form. (See, e.g., Yu at 9–10 (describing the invention with respect to thioridazine, cimetidine); Van den Dries Declaration ¶ 17.) As Dr. van den Dries explains, Yu’s “general formulation concept” is to neutralize an acidic pharmaceutical agent or a basic pharmaceutical agent to create the pharmaceutical salt, which salt is a deprotonated form of the free acid, i.e., neutralized, and thus is nonionic. (Id. ¶ 17.) Yu explains that one can add the salt of the pharmaceutical agent directly to the free pharmaceutical agent and “[i]n this way, the use of ionizing agents such as hydroxide or hydrogen ion to produce the desired ratio of ionization (neutralization) of the pharmaceutical is avoided or minimized.” (Yu 10: 39–48.) In view of these teachings of Yu, we do not agree with the Examiner that one of ordinary skill in the art would have added naproxen sodium to 2 Declaration of Dr. Kaspar van den Dries dated August 7, 2019. (Van den Dries Declaration at 9.) Dr. van den Dries is the “Senior Director of Science and Innovation, Softgels, Patheon Softgels Inc., a subsidiary of ThermoFisher Scientific Inc.” (Id. ¶ 4.) Appeal 2020-005453 Application 16/012,961 6 the Yu composition and would have also included an acid “in an amount of from 0.2 to 1.0 mole equivalents per mole of naproxen salt” as required by Appellant’s claim 1. As Dr. van den Dries explains, doing so would be “completely contradictory” to Yu because it would shift the salt form, which Yu teaches to form in order to balance the ionized naproxen free acid, from the salt form back to the protonated state, thereby upsetting the balance and creating more naproxen free acid, which is much less soluble than the ionic salt form. (Van den Dries Declaration ¶ 17.) This is true even in light of the Yu’s Example VIII, which is a composition of diclofenac sodium that includes hydrochloric acid (Yu 12:30–45), which the Examiner suggest supports the conclusion that Yu suggests inclusion of an acid in combination with a basic salt pharmaceutical agent. (Non-final Action 18.) According to the Examiner, “Yu teaches the solubility can be increased further even for basic salt compounds, such as diclofenac sodium . . . using hydrogen ions from HCl.” (See Appeal Br. 16 (referring to a prior Final Office Action dated April 24, 2019).) We disagree with the Examiner’s interpretation of Yu. As Appellant notes (Appeal Br. 16), Yu does not state that the hydrogen ions further increased the solubility of diclofenac sodium. There is no comparison in Yu to a diclofenac free acid formulation or to a diclofenac sodium composition without HCl; rather, there is simply an indication that the formulation made with the sodium diclofenac, polyethylene glycol, water, and HCl had 20% by weight concentration of diclofenac. (Yu 12:35; Appeal. Br. 16.) Furthermore, as Dr. Van den Dries explained “naproxen sodium is already highly soluble in aqueous and PEG solutions.” (Van den Dries Declaration ¶ 20.) Dr. Van den Dries notes that “[n]aproxen sodium has a Appeal 2020-005453 Application 16/012,961 7 solubility of 108 mM whereas “naproxen free acid has a water solubility of 69 μM. (Id. ¶ 19.) As Appellant notes, Yu discloses a formulation of naproxen free acid, potassium hydroxide, and polyethylene glycol 600 that has a 35.9% by weight concentration of naproxen. (Appeal Br. 17 (citing Yu 11:42–54 (Example IV)).) In addition, Dr. Van den Dries explains that naproxen sodium is twice as soluble as sodium diclofenac. (Id. ¶ 19.) Thus, even if it might be the case that HCl assisted in further solubilizing sodium diclofenac (which the current evidence of record does not suggest is the case), given the fact that naproxen and naproxen sodium have a significantly different solubility in water than diclofenac and diclofenac sodium and a significantly different chemical structure, there does not appear to be a reason suggested by Yu or any of the other cited references why it would be reasonable to add HCl to a fill formulation for a softgel that includes naproxen sodium. And even beyond that, as Appellant further explains regarding the claimed use of a weak acid as the “deionizing agent,” such as lactic acid: Strong acids like HCl are fully ionized (deprotonated) in solution, whereas weak acids do not completely ionize (deprotonate) in solution. Therefore, the purported effect [by the Examiner] of HCl on the solubility of diclofenac sodium, which is minimal (~4% as calculated by Appellant), is entirely incongruent with the potential and unknown effect of an organic acid on the solubility of naproxen sodium. (Reply Br. 9.)3 3 We note that the about 4% increase calculation arises from the difference between Yu’s identification of a 20% by weight concentrated composition compared to diclofenac sodium solubility in water of 15.91 mg/ml (e.g., about 15% by weight). (See Van den Dries Declaration ¶ 19 (noting the “Sodium salt [of diclofenac free acid] solubility: 15.91 mg/ml (54 mM)”).) Appeal 2020-005453 Application 16/012,961 8 In view of all of the foregoing, we find that one of ordinary skill in the art would not have found it obvious to have made softgel fill composition that includes sodium naproxen and a weak acid such as lactic acid in the mole equivalent range claimed based on the teachings of Yu example VIII with a reasonable expectation of success. We conclude the foregoing is true even considering the teachings of the remaining prior art the Examiner relied upon. Tanner simply teaches that naproxen is a free acid that is typically administered as naproxen sodium salt, and describes a fill formulation for use in a soft gel that includes naproxen sodium water and polyethylene glycol. (Tanner ¶¶ 66–68.) Tanner does not in any way suggest adding an acid to a naproxen salt formulation. Popp teaches that lactic acid is interchangeably used with fumaric acid in forming salts of active compounds. (Popp ¶ 58) That fact provides no suggestion to combine lactic acid (or fumaric acid for that matter) with a naproxen salt for any reason. Ulloa is of no consequence on the issue of the obviousness of including an acid in combination with a naproxen salt, as it merely mentions that naproxen can be added to pharmaceutical formulations of a non-sedating antihistamine combined with a nasal decongestant in order to address pain relief. (Ulloa ¶ 157, Abstract.) Thus, for the foregoing reasons, we do not affirm the Examiner’s rejection of claim 1 as being obvious from Yu, Tanner, Popp, and Ulloa. For the same reasons, we also do not affirm the Examiner’s rejection of independent claim 13 as being obvious from Yu, Tanner, Popp, and Ulloa, which claim requires naproxen sodium rather than simply a naproxen salt as in claim 1, as well as specifying particular solubilizers. The remaining Appeal 2020-005453 Application 16/012,961 9 claims are dependent claims on either claim 1 or claim 13. Thus, we do not affirm the Examiner’s rejection of those claims as being obvious from Yu, Tanner, Popp, and Ulloa. In re Fine, 837 F.2d 1071, 1076 (Fed. Cir. 1988) (“Dependent claims are nonobvious under section 103 if the independent claims from which they depend are nonobvious.”). DECISION SUMMARY Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–10, 13–22 103(a) Yu, Tanner, Popp, Ulloa 1–10, 13–22 REVERSED Copy with citationCopy as parenthetical citation