Doxey, RyanDownload PDFPatent Trials and Appeals BoardMar 23, 202014381370 - (D) (P.T.A.B. Mar. 23, 2020) 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. 14/381,370 08/27/2014 Ryan Doxey 9729-40TS 9306 20792 7590 03/23/2020 MYERS BIGEL, P.A. PO BOX 37428 RALEIGH, NC 27627 EXAMINER ALLEY, GENEVIEVE S ART UNIT PAPER NUMBER 1617 MAIL DATE DELIVERY MODE 03/23/2020 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 RYAN DOXEY ____________ Appeal 2019-003847 Application 14/381,370 Technology Center 1600 ____________ Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1,2 under 35 U.S.C. § 134(a) involving claims to nitric oxide releasing pharmaceutical compositions. The Examiner rejected the claims as obvious. 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. Appellant identifies the Real Party in Interest as Novan Inc. (see Appeal Br. 2). 2 We have considered and herein refer to the Specification of Aug. 27, 2014 (“Spec.”); Final Office Action of Apr. 25, 2018 (“Final Act.”); Appeal Brief of Oct. 25, 2018 (“Appeal Br.”); Examiner’s Answer of Feb. 15, 2019 (“Ans.”); and Reply Brief of Apr. 15, 2019 (“Reply Br.”). Appeal 2019-003847 Application 14/381,370 2 Statement of the Case Background “Numerous skin diseases or disorders result from inflammation with the associated release of mediators from a variety of inflammatory and resident cells” (Spec. ¶ 3). Delivery of a moisture activated therapeutic agent “should be provided without substantial irritation or exacerbation of the inflammatory condition” (id. ¶ 4). Aqueous vehicles may be inappropriate for moisture activated therapeutic agents; however, mineral oil ointments may reduce the effectiveness of the therapeutic agent when applied (id.). “The present invention provides pharmaceutical composition that may be administered topically . . . [that] may comprise . . . a hydrophobic base, [] an amphiphilic compound . . . [and] a moisture activated active pharmaceutical ingredient.” (id. ¶ 27). The Claims Claims 1, 3, 7–10, 12–14, 18–21, and 25–31 are on appeal.3 Independent claim 1 is representative and reads as follows: 1. A nitric oxide (NO)-releasing pharmaceutical composition, the NO-releasing pharmaceutical composition comprising: a hydrophobic base present in the NO-releasing pharmaceutical composition at a concentration from about 35% to about 90% by weight of the NO-releasing pharmaceutical composition; an amphiphilic compound present in the NO-releasing pharmaceutical composition at a concentration from about 1% to about 30% by weight of the NO-releasing pharmaceutical composition, wherein the amphiphilic compound is a polyethylene glycol (PEG) caprylic/capric glyceride; 3 Claims 22 and 23 were withdrawn and claims 2, 4–6, 11, 15–17, and 24 were cancelled (see Appeal Br. 16–19). Appeal 2019-003847 Application 14/381,370 3 water at a concentration of less than about 2% by weight of the NO-releasing pharmaceutical composition; and diazeniumdiolate-functionalized polysiloxane macromolecules that are NO-releasing co-condensed silica particles. (Appeal Br. 16). The issues The Examiner rejected claims 1, 3, 7–10, 14, 18–21, and 25–30 under 35 U.S.C. § 103(a) as obvious over Stasko4 and Embil5 (Final Act. 3–9). The Examiner rejected claims 12 and 13 under 35 U.S.C. § 103(a) as obvious over Stasko, Embil, and Barthez6 (Final Act. 9–11). Because both of these rejections rely on the same combination of references, and Barthez is added solely to address 1–25 wt.% of a humectant that comprises a polyhydric alcohol (see Final Act. 10), we consider these rejections together. The Examiner finds Stasko teaches topical non-aqueous gel compositions containing diazeniumdiolate-functionalized polysiloxane macromolecules that are nitric oxide (NO)-releasing co-condensed silica particles (NitricilTM) (Final Act. 4–5). The compositions may include 1–10% NitricilTM, 10–90 wt.% mineral oil (a hydrophobic base), 5–20 wt.% cyclomethicone (a hydrophobic polymer and siloxane), 25–55 wt.% caprylic or capric triglyceride (a co-solvent), and 10–85 wt.% isopropyl myristate (an amphiphilic compound) (id.). The Examiner finds that any differences in 4 Stasko et al., WO 2011/022652 A1, published Feb. 24, 2011. 5 Embil et al., WO 2012/001403 A1, published Jan. 5, 2012. 6 Barthez et al., US 2010/0286285 A1, published Nov. 11, 2010. Appeal 2019-003847 Application 14/381,370 4 concentration between the prior art components and the claimed components would have been the obvious result of routine experimentation (id. at 7). The Examiner finds Stasko does “not specifically teach wherein the amphiphilic compound is PEG-6 caprylic/capric glyceride at a concentration of from about 1% to less than 5% by weight” (id. at 6). The Examiner finds that Embil teaches topical compositions substantially free from water that include flurbiprofen and 1–10 wt.% polyglycerides, such as PEG-6 caprylic capric glyceride (id.). PEG-6 caprylic capric glyceride functions as a co- solvent and skin penetration enhancer (id.). The Examiner finds Stasko and Embil teach nonaqueous pharmaceutical compositions used for topical drug delivery of anti-inflammatory drugs, e.g., flurbiprofen (id. at 8). The Examiner determines “it would have been prima facie obvious for a person of ordinary skill in the art to combine their respective teachings and to incorporate 1–10% by weight PEG-6 caprylic/capric glycerides into the composition of [Stasko], with a reasonable expectation of success, at the time of the instant application” (id.). The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that the combination of Stasko, Embil, and Barthez renders the claims obvious? Findings of Fact (“FF”) 1. Stasko teaches topical gels including 0.1–20 wt.% NO-releasing diazeniumdiolate-functionalized polysiloxane macromolecules and a hydrophobic, non-aqueous gel base (Stasko ¶¶ 8–10). 2. Stasko teaches the NO-releasing macromolecules may have a hydrodynamic range of 1–100 nm, “which may maximize trans-epidermal skin penetration and enhance nitric oxide delivery to deeper skin structures” Appeal 2019-003847 Application 14/381,370 5 or a hydrodynamic range of 101–1000 nm which may “limit skin penetration, systemic absorption, and any resulting toxicity of the macromolecular scaffold . . . . Selective delivery to the stratum corneum, epidermis or dermis may be achieved by varying the particle size” (Stasko ¶ 71). 3. Stasko teaches that: The properties of the topical gels, including the NO- release profile may be tailored by the selection of the gel composition. The gels may also provide beneficial or therapeutic action to the skin or wound bed (e.g., moisturize, absorb wound exudate, provide an occlusive barrier, etc.) that may directly affect skin conditions or wound healing. The excipients that form the gels may also indirectly affect wound healing by affecting the stability of the diazeniumdiolate- functionalized polysilane macromolecules or other therapeutic agents within the medicament. (Stasko ¶ 74). 4. Stasko teaches “excipients for use in topical gels are well- known in the art . . . Exemplary excipients may include” humectants, glycerol, polyethylene glycols, solvents, and emollients, e.g., glycerine and pentylene glycol. “Emollients may be useful to prevent stratum corneum dehydration occurring due to the use of anhydrous solvents in the formulation” (Stasko ¶ 75). 5. Stasko teaches polymers may act as excipients, including hydrophobic polymers, e.g., polysiloxanes and polyethylene. Compositions containing hydrophobic polymers may include 60–70 wt.% silicon elastomer (Stasko ¶¶ 79, 105). Appeal 2019-003847 Application 14/381,370 6 6. Stasko teaches surfactants may be used to reduce the interfacial surface energy and “may facilitate spreading of the ointment or liquid over a wider area” (Stasko ¶ 84). 7. Stasko teaches “[e]xemplary solvent excipients that may be useful in hydrophobic formulations may include capric/caprylic triglycerides, isopropyl myristate, [and] mineral oil” (Stasko ¶ 86). 8. Stasko teaches “[i]n addition to the diazeniumdiolate- functionalized polysiloxane macromolecules and excipients, the topical gels may also include at least one additional therapeutic agent such as . . . anti- inflammatory agents,” e.g., “flurbiprofen” (Stasko ¶¶ 87, 92). 9. Stasko teaches a gel including: diazeniumdiolate-functionalized polysiloxane macromolecules, caprylic or capric triglyceride at a concentration in a range of 25 to 55 weight percent; fumed silica at a concentration in a range of 4 to 8 weight percent; cyclomethicone at a concentration in a range of 5 to 20 weight percent; optionally, isopropyl myristate at a concentration in a range of 10 to 85 weight percent; and optionally, mineral oil at a concentration in a range of 10 to 90 weight percent. (Stasko ¶ 112). 10. Embil teaches topical flurbiprofen-containing compositions useful for treating conditions associated with inflammation and pain (Embil 1). 11. Embil teaches the “compositions are substantially free from water (i.e., they are substantially anhydrous)” and include a solubilizing system (Embil 3.) Appeal 2019-003847 Application 14/381,370 7 12. Embil teaches the solubilizing system may include co-solvents having skin penetration enhancing properties, including polyoxyglycerides, such as PEG-6-caprylic/capric glyceride (Embil 5). 13. Embil teaches the polyoxylgyceride co-solvent may be present in a concentration of 1–10 wt.% (Embil 8). 14. Barthez teaches an anhydrous ointment containing a water sensitive active ingredient and an emollient to promote the well-being of skin (Barthez ¶¶4, 69). 15. The emollient may include liquid fatty acid substances, including humectants such as polyols or glycerol, in an amount of 0.01–30 wt.% (Barthez ¶¶ 69, 71, 78). Principles of Law “In determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls. . . . [A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419–20 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 3–9; FFs 1–15) and agree that the claims are rendered obvious by Stasko, Embil, and Barthez. We address Appellant’s arguments below. Appellant argues “[t]here is no reason to select a [PEG] caprylic/capric glyceride in a composition as claimed” (Appeal Br. 4, emphasis omitted). Appellant contends both Stasko’s isopropyl myristate Appeal 2019-003847 Application 14/381,370 8 and Embil’s PEG caprylic/capric glyceride are optional components, chosen from a “laundry list” of excipients (id. at 5–7). Appellant argues “[t]he disclosure in Stasko of isopropyl myristate fails to describe or suggest a PEG caprylic/capric glyceride” (id. at 5, emphasis omitted). Appellant argues that “Embil fails to provide the requisite motivation or suggestion to specifically select and include a PEG caprylic/capric glyceride in the compositions of Stasko” (id. at 6, emphasis omitted). More specifically, Appellant contends that Embil describes a solubilizing system for a small molecule active agent, e.g., flurbiprofen (id. at 6). Appellant contends that the solubilizing system forming a solution would not have been used for a diazeniumdiolate-functionalized polysiloxane macromolecule particulate (id.). Appellant submits a Declaration7 by the Inventor, attesting that one skilled in the art would not “have had any reason to believe that a PEG-8 caprylic/capric glyceride could be used to increase percutaneous absorption of the diazeniumdiolate- functionalized polysiloxane macromolecules of Stasko, particularly since it would require absorption of a particulate” (id., citing Decl. ¶ 11). We find these arguments unpersuasive. Appellant’s claim 1 recites “the NO-releasing pharmaceutical composition comprising . . . .” (Appeal Br. 16, 19). “Comprising is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.” Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1344–45 (Fed. Cir. 2003). 7 Declaration of Ryan Doxey dated Jun. 9, 2017 (“Decl.”) We note that the Declaration addresses a different rejection than that currently pending and does not directly address the obviousness of combining Embil with Stasko (see Doxy Decl. ¶¶ 4, 8). Appeal 2019-003847 Application 14/381,370 9 We note that Appellant’s Specification teaches that “combinations of [active pharmaceutical ingredients] may be included in the compositions”; that “[e]xamples of anti-inflammatory agents include . . . flurbiprofen”; and that “[a]ny suitable NO-releasing compound may be used in a pharmaceutical composition” “[i]n some embodiments, the nitric oxide- releasing compound comprises diazeniumdiolate-functionalized polysiloxane” (Spec. ¶¶ 46, 53, 57, 61). Thus, when the term “comprising” in claim 1 is read in light of a Specification that expressly contemplates compositions with combinations of active pharmaceutical agents including flurbiprofen and NO-releasing compounds, we interpret claim 1 to allow for additional active components, e.g., flurbiprofen, and additional excipients other than those claimed. “[D]uring examination proceedings, claims are given their broadest reasonable interpretation consistent with the specification.” In re Hyatt, 211 F.3d 1367, 1372 (Fed. Cir. 2000). Both Stasko and Embil teach anhydrous compositions for treating inflammation that may include flurbiprofen (FFs 8, 10, 11). Both Stasko and Embil teach compositions containing hydrophobic bases and amphiphilic compounds, e.g., isopropyl myristate and PEG caprylic/capric glycerides, respectively (FFs 1, 7, 9, 12, 13). Stasko suggests the anhydrous compositions may be modified to improve NO-release, provide benefits to the skin or wound bed, and incorporate excipients that improve the stability of other therapeutic compounds in the formulation, e.g., flurbiprofen (FF 3). Embil teaches solvent systems including PEG-6-caprylic/capric glyceride to enhance penetration of flurbiprofen (FF 12). Because Stasko teaches that compositions may be modified to improve the therapeutic properties of Appeal 2019-003847 Application 14/381,370 10 NitricilTM and additional active agents, a person of ordinary skill in the art would have been motivated to improve the composition for delivering flurbiprofen as taught by Embil. Therefore, we agree with the Examiner that the prior art provides a reason for combining the references in the manner claimed. We also do not find the “laundry list” argument persuasive. Simply because the prior art “discloses a multitude of effective combinations does not render any particular formulation less obvious.” Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). “[P]icking and choosing may be entirely proper in the making of a 103, obviousness rejection.” In re Arkley, 455 F.2d 586, 587 (CCPA 1972). Appellant does not identify a secondary consideration demonstrating criticality or anything unexpected about the combination of two known prior art pharmaceutical agents (FF 1, 8). Appellant further argues the “combination fails to provide a reasonable expectation of success” (Appeal Br. 7, emphasis omitted). Appellant contends that the “compositions of Embil are distinctly different than those of Stasko in that the composition[s] of Embil comprises a glycol ether and glycol ester and are for solubilizing flurbiprofen” (id. at 7–8). Appellant argues that there is no teaching that optional compounds for solubilizing a small molecule active agent would have been suitable for the diazeniumdiolate functionalized macromolecules of Stasko. Appellant contends “Stasko describes embodiments to selectively accumulate diazeniumdiolated macromolecules in the stratum corneum and limit skin penetration” (id. at 8, citing Stasko ¶¶ 71, 102). Appeal 2019-003847 Application 14/381,370 11 We are not persuaded by Appellant’s argument. As discussed above, the Examiner has identified a reason in the prior art to combine the references. The combined prior art teaches topical compositions containing the same anhydrous excipients, used for the same purpose, i.e., treating inflammation. Moreover, Stasko teaches varying the particle size of the diazeniumdiolated macromolecules may limit skin penetration or may maximize skin penetration (FF 2, emphasis added). Contrary to Appellant’s argument, Stasko teaches that a person of ordinary skill in the art would have had a reasonable expectation of success in varying the parameters of the diazeniumdiolated macromolecules, excipients, and additional active agents, e.g., flurbiprofen, as combined with Embil, to obtain a therapeutically effective composition. “Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). Finally, Appellant contends the Examiner relies on impermissible hindsight by using the Specification as a guide (Appeal Br. 5). We are not persuaded. Because the Examiner “takes into account only knowledge that was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure,” reconstructing the composition is proper. In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Claim 19 Appellant argues claim 19 is separately patentable from claim 1 (Appeal Br. 8). Appellant repeats the argument against combining Stasko and Embil, discussed above as to claim 1 (id. at 8–9). Appellant further argues that Stasko does not describe or suggest a composition containing Appeal 2019-003847 Application 14/381,370 12 35–80 wt.% hydrophobic hydrocarbon polymer, 1–20 wt.% mineral oil, and 1–20 wt.% PEG caprylic/capric glyceride (id. at 9). Appellant argues “Embil fails to even mention mineral oil and does not describe a hydrophobic hydrocarbon polymer” (id.). We are not persuaded by Appellant’s argument. Appellant argues against the separate teachings of Stasko and Embil and not the combination. “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). The combination of Stasko and Embil teaches a hydrophobic hydrocarbon polymer (polyethylene), mineral oil, and a PEG caprylic/capric glyceride, along with overlapping ranges of these or functionally similar excipients (FFs 5, 7, 9, 12, 13). Stasko and Embil teach modifying the amount of excipients to optimize the delivery of active agents, including, e.g., flurbiprofen (FFs 3, 12). “The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. These cases have consistently held that in such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range.” In re Woodruff, 919 F. 2d 1575, 1578, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990) (internal citations omitted). Appellant has not provided any evidence showing that the claimed ranges are critical. Appeal 2019-003847 Application 14/381,370 13 Claims 12 and 13 Appellant contends claims 12 and 13 are separately patentable (Appeal Br. 9–11). Appellant argues that the prior art does not teach a polyhydric alcohol humectant at a concentration from about 1–25 wt.% of the composition (id.). Appellant contends Barthez’s compositions containing solubilized vitamin D are distinctly different from Stasko’s compositions containing an insoluble particulate and thus the references cannot be combined (id. at 10). We are not persuaded by Appellant’s argument. As discussed above, Stasko teaches compositions that may provide a number of benefits, in addition to topical application of NO-releasing compounds. For example, the composition may provide other beneficial or therapeutic action to the skin and thus include humectants to promote skin well-being as taught by Barthez (FFs 3, 14). Moreover, both Stasko and Barthez teach topical compositions including humectants, e.g., polyhydric alcohols, such as glycerol and pentylene glycol (FFs 4, 14, 15). Because the prior art teaches the benefits to the skin of including 0.01–30 wt.% of a polyhydric alcohol humectant, we agree with the Examiner that a person of ordinary skill in the art would have been motivated to combine the references. Claims 25–31 Appellant argues claims 25–31 are separately patentable (Appeal Br. 11–14). However, Appellant merely restates the limitations of the claims and repeats the previous arguments against combining Stasko and Embil. (see id.). As to claim 29, Appellant further contends the prior art does not teach the claimed ranges of mineral oil and PEG caprylic/capric glyceride, Appeal 2019-003847 Application 14/381,370 14 and the Examiner has not established that it would have been “obvious to try” the claimed amounts (id. at 13). We are not persuaded by Appellant’s arguments. With respect to claims 25–28, 30, and 31, we sustain the Examiner’s rejection for the reasons set forth above, namely that a person of ordinary skill in the art would have been motivated to combine Stasko and Embil, with a reasonable expectation of success in the combination. As to claim 29, Appellant has not provided any evidence of criticality for the claimed ranges (as discussed above for claim 19). Thus, we sustain the Examiner’s rejection. Conclusion of Law A preponderance of the evidence of record support the Examiner’s conclusion that claims 1, 3, 7–10, 12–14, 18–21, and 25–31 would have been obvious over the combined prior art. DECISION In summary: Claims Rejected 35 U.S.C. § Reference(s)Basis Affirmed Reversed 1, 3, 7–10, 14, 18–21, 25–31 103(a) Stasko, Embil 1, 3, 7–10, 14, 18–21, 25–31 12, 13 103(a) Stasko, Embil, Barthez 12, 13 Overall Outcome 1, 3, 7–10, 12–14, 18–21, 25–31 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED Copy with citationCopy as parenthetical citation