CuriNanoRx, LLCDownload PDFPatent Trials and Appeals BoardApr 12, 20212020005497 (P.T.A.B. Apr. 12, 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. 15/593,586 05/12/2017 Indu JAVERI 21562-0103 5211 164114 7590 04/12/2021 Verrill Dana, LLP One Federal Street, 20th Floor Boston, MA 02110 EXAMINER KISHORE, GOLLAMUDI S ART UNIT PAPER NUMBER 1612 NOTIFICATION DATE DELIVERY MODE 04/12/2021 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): kwalmsley@verrilldana.com lhymel@verrilldana.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte INDU JAVERI and KALIAPPANADAR NELLAIAPPAN Appeal 2020-005497 Application 15/593,586 Technology Center 1600 Before DONALD E. ADAMS, RYAN H. FLAX, 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 directed to a method of incorporating hydrophobic therapeutic agents into preformed liposomes as being obvious. Oral argument was heard on March 23, 2021. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 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 CuriNanoRx, LLC. Appeal Br. 3. Appeal 2020-005497 Application 15/593,586 2 STATEMENT OF THE CASE “Liposomes are microscopic lipid vesicles that are composed of a central aqueous cavity surrounded by a lipid membrane formed by concentric bilayer(s) (lamellas).” (Spec. 1.) “Liposomes can be unilamellar vesicles (“UMV”), having a single lipid bilayer[.]” (Id.) “The properties of the liposomes depend, among other factors, on the nature of the constituents.” (Id. at 2.) “There are numerous combinations of phospholipids, optionally with other lipids or cholesterol, in an aqueous medium to obtain liposomes. Depending on the method of preparation and the lipids used, it is possible to obtain vesicles of different sizes, structures, and properties.” (Id.) “The bioavailability of a pharmaceutical drug depends largely in part on the solubility and stability of the drug.” (Id. at 1.) It is known that encapsulating drugs in a liposome bilayer can be accomplished to improve its biovailability. (Id.; see also id. at 3–4 (citing prior art methods).) Appellant’s invention is directed to methods for incorporating a hydrophobic therapeutic agent into liposomes. (Id. at 5.) Claims 1 and 25, reproduced below, are illustrative of the claimed subject matter: 1. A method of incorporating a hydrophobic therapeutic agent into preformed liposomes, the method comprising the steps of: (a) providing (i) a liposome suspension comprising a plurality of preformed unilamellar liposomes having an average size less than about 100 nm suspended in an aqueous medium, the liposomes comprising lipid forming a lipid bilayer phase, and (ii) a solid form of a hydrophobic therapeutic agent; (b) adding the solid form of the hydrophobic therapeutic agent to the liposome suspension, thereby forming a liposome- drug suspension; Appeal 2020-005497 Application 15/593,586 3 (c) homogenizing the liposome-drug suspension; whereby the hydrophobic therapeutic agent is incorporated into the lipid bilayer phase; and (d) lyophilizing the homogenized liposome-drug suspension; wherein step ( c) is performed at a temperature at or below ambient temperature; and wherein steps (b) and (c) are performed in the absence of solvent and in the absence of surfactant. 25. A method of incorporating a hydrophobic therapeutic agent into preformed liposomes, the method comprising the steps of: (a) providing (i) a liposome suspension comprising a plurality of preformed unilamellar liposomes having an average size less than 100 nm suspended in an aqueous medium, the liposomes comprising lipid forming a lipid bilayer phase, and (ii) a therapeutic agent concentrate comprising a hydrophobic therapeutic agent dissolved in a liquid medium comprising or consisting of solvent; (b) adding the therapeutic agent concentrate to the liposome suspension to form a liposome-drug suspension, wherein the total concentration of solvent in the liposome-drug suspension is not more than 10 weight percent; (c) homogenizing the liposome-drug suspension; whereby the hydrophobic therapeutic agent is incorporated into the lipid bilayer phase; and (d) lyophilizing the homogenized liposome-drug suspension; wherein step (c) is performed at a temperature at or below ambient temperature; and wherein steps (b) and (c) are performed in the absence of surfactant. Appeal 2020-005497 Application 15/593,586 4 REFERENCES The prior art relied upon by the Examiner is: Name Reference Date Hope US 2002/0094344 A1 July 18, 2002 Daftary et al. US 2005/0142178 A1 June 30, 2005 Desai et al. US 2007/0178147 A1 Aug. 2, 2007 Leigh et al. US 2008/0131499 A1 June 5, 2008 Haas et al. US 2011/0002851 A1 Jan. 6, 2011 Ali et al. WO 2008/127358 A22 Oct. 23, 2008 REJECTIONS Claims 1, 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Leigh alone or in combination with WO ’358. (Non-Final Action 2). Claims 1, 4–8, 11–16, 18, 20–24 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Leigh, Desai, and Hass. (Non-Final Action 4.) Claims 1, 4–8, 11–31, 33–37, and 40–45, 47, 49–513 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over WO ’358 alone or in combination with Daftary and Leigh. (Non-Final Action 5.) Claims 25–31, 33–37, 40–45, 47, and 49–51 are rejected under pre- AIA 35 U.S.C. § 103(a) as being unpatentable over WO ’358 by itself or in combination with Daftary, Leigh, and Hope. (Non-Final Action 8.) 2 Although the Examiner and Appellant have called it “WO,” “WO 2008,” and “Jina,” herein we refer to this reference as “WO ’358.” 3 As claims 46 and 48 have been canceled and claims 52–54 are not of record, we find the Examiner’s statement of rejection including those claims to be an inadvertent error. Appeal 2020-005497 Application 15/593,586 5 Claims 25–31, 33–37, 40–45, 47, and 49–51 are rejected under pre- AIA 35 U.S.C. § 103(a) as being unpatentable over Hope, Desai, and Hass. (Non-Final Action 9.) Claims 1, 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1–5 of U.S. Patent No. 8,591,942. (Non-Final Action 11.) DISCUSSION I. Obviousness Rejections Involving Independent Claim 1 The Examiner makes three separate rejections of claim 1 over varying combinations of the prior art. However, two of the rejections rely on the combination of Leigh and WO ’358 prior art. We address that combination below. Appellant’s claim 1 requires homogenization take place at or below ambient temperature and that the addition of a hydrophobic agent to a liposome suspension and homogenization take place in the absence of both a solvent and a surfactant. The Examiner finds that Leigh teaches a method of loading a hydrophobic drug into preformed liposomes where the lipophilic drug may be in solution such as ethanol or may be present as a lyophilized powder which is added to a liposomal suspension to incorporate the drug compound in the liposome. (Non-Final Action 2–3, 4 (citing Leigh “Examples, 7 and 8 in particular”); id. at 4 (“Leigh clearly teaches that the hydrophobic drug is added as a solid”); Ans. 10 (citing Leigh ¶¶ 32, 49).) The Examiner notes that Leigh teaches that liposomes sizes are less than 40 nm in diameter (Non-Final Action 2) and teaches that preparation by high pressure Appeal 2020-005497 Application 15/593,586 6 homogenization or extrusion “implies small unilamellar liposomes” (Ans. 10 (citing Leigh ¶35)). The Examiner finds further that “[a]ssuming that the gentle swirling of the liposomal mixture is not homogenization as argued by applicant, one of ordinary skill in the art would use any suitable means such as high pressure homogenization or extrusion which are also taught by Leigh in paragraph 0035 to obtain the total incorporation of the hydrophobic therapeutic agent into the lipid bilayer since these techniques are known in the art to reduce the sizes of liposomes as evident from Leigh.” (Non-Final Action 3; see also Non-Final Action 4–5; Ans. 10.) According to the Examiner, “[w]hat is lacking in Leigh is the lyophilization of liposomes.” (Non-Final Action 3, 4.) The Examiner finds, however, that lyophilization of liposomes was common practice in the liposomal art for storage purposes, citing as examples, WO ’358, Desai, and Haas. (Non-Final Action 4, 5.) The Examiner concludes that it would have been obvious to one having skill in the art to lyophilize the liposomes of Leigh “since lyophilization of liposomes for storage purposes is a common practice in the art as evident from WO [’358].” (Id.) Regarding Desai, the Examiner finds that it teaches “that liposomes loaded with hydrophobic drugs can be stored after a lyophilization for years or more.” (Id. at 5.) The Examiner notes that Haas teaches lyophilization of a paclitaxel containing liposome that has more than 18 month shelf-life. (Id.) The Examiner also notes that Haas teaches that it was known in liposomal preparation art that such preparations can be obtained by homogenizing the hydrophobic compound, where homogenization includes “mechanical mixing, stirring, [and] high-pressure homogenization.” (Id.) Appeal 2020-005497 Application 15/593,586 7 The Examiner finds that WO ’358 teaches encapsulation in liposomes of at least one hydrophobic drug, such as amphotericin or paclitaxel, with or without deoxycholate as a solvent, and subsequently lyophilizing the drug loaded liposomes. (Id. at 6, 3.) The Examiner explains that the WO ’358 process in the examples involves suspension of the drug in an aqueous medium and mixing that with cholesteryl sulfate and soya phosphatidylcholine, which mixture is then subject to high pressure homogenization and that the temperature is either room temperature or at a desired temperature. (Id.) The Examiner finds that WO ’358 teaches that cholesterol can be used as an alternative to cholesteryl sulfate (Ans. 10 (citing WO ’368 16:10–13).) Moreover, the Examiner finds that “[i]t is well-known in the art that cholesterol is [a] liposomal membrane rigidifying agent and therefore, it would have been obvious to one of ordinary skill in the art that [WO ’358] is using cholesterol or its derivatives as a membrane rigidifying agent.” (Id. at 10–11) The Examiner states that the process of WO ’358 differs from the claimed process in that the encapsulation of the hydrophobic drug and hydration of phospholipid occurs simultaneously in WO ’358, when the phospholipid is hydrated with an aqueous medium and the hydrophobic active. (Non-Final Action 6.) The Examiner explains that the lipid bilayer forms quickly when the phospholipid is hydrated. (Id. at 5–6.) And, in any event, the Examiner finds that Leigh and Daftary teach that hydrophobic active agents could be loaded into liposomes after the formation of those liposomes. (Id. at 7.) In light of the teachings of the references, the Examiner finds that one of ordinary skill in the art would have found it obvious to use a high pressure Appeal 2020-005497 Application 15/593,586 8 homogenization technique to incorporate the hydrophobic drug compound in Leigh because WO ’358 teaches using such a technique. (Id. at 3.) The Examiner finds that it would have been obvious to add the hydrophobic drug compound to preformed liposomes in WO’358 in light of the fact that both Leigh and Daftary teach doing so is known in the art. (Id. at 7.) We agree with the Examiner that Leigh in combination with WO’358 renders claim 1 obvious. WO ’358 teaches that “there is a need for processes for preparation of lipid based formulations without the need for . . . organic solvents.” (WO ’358 ¶ 2.) WO ’358 also teaches a method in which the active ingredient can be added “after the preparation of the liposome system,” and that the liposome formulation is prepared without using organic solvent. (Id. ¶¶ 13, 37 (“For example, in some embodiments, the active ingredient in dry form may be dispersed or emulsified into an aqueous unloaded liposome system”), 43 (“[t]he invention method is simple, rapid and less expensive method to produce organic solvent-free aqueous liposome systems”).) WO ’358 teaches that a suspension of phospholipid, active compound and cholesteryl derivative in water or buffer is homogenized or sonicated at any desired temperature range from 20–60 ºC. (Id. ¶¶ 114–116.) Leigh teaches a “method of loading poorly soluble compounds into previously formed, aqueous suspensions of lipid particles” where the “average lipid particle size is below 1000 nm, preferably below 300 nm.” (Leigh ¶ 69.) Indeed, Leigh further states that it is most preferred that the phospholipid containing liposome be below 100 nm. (Id. ¶ 35.) Leigh notes that: Appeal 2020-005497 Application 15/593,586 9 Surprisingly it has been found that an aqueous suspension of finely divided lipid particles, i.e. preformed particles comprising at least one membrane lipid as the major component or constituent has a much higher capacity for solubilising lipophilic compounds if the compound is added to already formed lipid particles and not dissolved in a lipid solution during formation of the particles, which is usually the case in the prior art. (Id. ¶ 33; see also id. ¶ 22.) Leigh further explains that “[b]ecause of the lipophilicity of the compound and the extensive surface area presented by the discrete lipid particles, the compound partitions preferentially into the lipid and forms molecular associates.” (Id. ¶ 32 (emphasis added).) Although Leigh teaches that the “fully loaded lipid suspension” may be prepared just prior to use, it also discloses that for those “compounds that are more stable,” “the lipid suspension may be lyophilised.” (Id. ¶ 36.) Example 8 of Leigh describes the method generally whereby a dry form of a lipophilic drug is mixed with an aqueous dispersion of lipid particles to thereby “load the lipophilic drug” into the lipid particle. (Leigh ¶¶ 67–68 (Example 8).) Though the method is only generally described in Example 8, we understand from the description at paragraphs 22 and 32–33 that the preferential partition of the lipophilic drug into a lipid particle occurs “spontaneously and instantaneously” when the aqueous suspension of finely divided preformed lipid particles comprising at least one membrane lipid as the major component or constituent when the lipophilic drug is added without first being dissolved in a lipid solution during formation of the particles. Although Leigh indicates that “[o]nly minimum agitation is required” (Id. ¶ 69), we note that Leigh also teaches that association efficiency may only be 80%. (Id. ¶ 36). Thus, we agree with the Examiner that it would Appeal 2020-005497 Application 15/593,586 10 have been obvious to homogenize the mixture such as was known to be done for liposome drug loading (see, e.g., WO ’358 ¶ 114). We understand that such homogenization, which involves shear stress, would facilitate temporary disruption of the lipsome bilayer of the lipid particles. (See, e.g., Hope ¶ 7.) Moreover, we agree with the Examiner that it would have been obvious to lyophilize the loaded liposome suspension as suggested in Leigh (Leigh ¶ 36), and as taught by other prior art references, such as WO’358 for longer term storage of the loaded liposome (WO ’358 ¶ 44). Appellant argues that the Examiner’s rejection of claim 1 combining Leigh and WO ’358 is in error because WO ’358 “requires the use of cholesteryl sulfate, a surfactant, to disrupt lipid bilayer structure to aid the incorporation of hydrophobic drugs” and that “the Examiner wrongly asserts that cholesteryl sulfate is not a surfactant” when that compound “has a negatively charged head group and a hydrophobic portion (acylated sterol ring), which clearly fits the structural paradigm for surfactants.” (Appeal Br. 9, 11, 12; Reply Br. 5, 6.) In addition, Appellant argues that Example 8 of Leigh, “[t]he only portion of Leigh that is marginally relevant” to the claimed invention “which requires incorporation of drug into preformed liposomes” (id. at 8), has “no details . . . revealed about the nature (e.g., size and lamellarity) of the resulting liposomes” and it “lacks the homogenization step of Appellant’s claims, instead performing ‘swirling’ (which the average skilled person would not regard as homogenization)” (id.). Appellant also argues that “Example 8 includes no specific protocols or method details, and the entire approach is different from the methods described in the rest of Leigh. Thus, the only relevant portion of Leigh lacks sufficient information to provide an enabling disclosure of Appellant’s method of claim 1.” (Id. at Appeal 2020-005497 Application 15/593,586 11 8–9.) In light of the foregoing, Appellant argues that “Leigh alone fails to teach or suggest every limitation of claim 1” and WO ’358 “does not cure the defect of Leigh” because it only teaches the use of “surfactant-containing liposomes which are excluded from claim 1.” (Id. at 11.) Moreover, Appellant argues that “[o]nly Example 8 of Leigh suggests a method of adding a solid drug to liposomes, but the liposomes are uncharacterized due to lack of any detailed description” and thus claim 1 is not obvious over WO ’358 and Leigh. (Id. at 12.) We do not find Appellant’s arguments persuasive to establish non- obviousness of the method recited by claim 1. In particular, Appellant’s argument rests on the false premise that “[i]t was expected at the time of Leigh and at the time of the present invention that hydrophobic agents could only be incorporated into lipid bilayer (liposomal) membranes by first disrupting the bilayer structure using surfactants or solvents, or by pre- mixing the lipid and hydrophobic agent in a solvent solution or in mixed lipid-surfactant micelles prior to formation of the liposomes.” (Reply Br. 4 (emphasis added).) Appellant argues that prior to the claimed invention the expectation was that hydrophobic drugs were not able to “overcome the polar and charged bilayer surface and access the hydrophobic bilayer core without surfactants and without the need to add the drug to the lipid-organic solvent solution prior to liposome formation.” (Appeal Br. 5.) However, Leigh teaches that it was found that the association of a lipophilic compound (one with a low solubility in aqueous medium) with a liposome could be accomplished by mixing it with the preformed and finely divided lipid particles where the particles are in aqueous suspension and not dissolved in a lipid solution during formation of the particles and the lipophilic compound Appeal 2020-005497 Application 15/593,586 12 is not in a solvent. (Leigh ¶¶ 22, 33.) In particular, as we have already noted above, Leigh states: Surprisingly it has been found that an aqueous suspension of finely divided lipid particles, i.e. preformed particles comprising at least one membrane lipid as the major component or constituent has a much higher capacity for solubilising lipophilic compounds if the compound is added to already formed lipid particles and not dissolved in a lipid solution during formation of the particles, which is usually the case in the prior art. (Leigh ¶ 33.) Leigh explains that “[b]ecause of the lipophilicity of the compound and the extensive surface area presented by the discrete lipid particles, the compound partitions preferentially into the lipid and forms molecular associates,” a process which it calls “Instant Partition Loading.” (Id. ¶ 32.) And Leigh teaches that this association is, upon mixing, “spontaneous[] and instantaneous[].” (Id. ¶ 22: Unexpectedly, it has been found that the present invention allows compounds which have low solubility in aqueous media to form molecular associates spontaneously and instantaneously with membrane lipid suspensions comprising discrete particles wherein the major constituent is at least one membrane lipid, when they are mixed together.) In short, Leigh specifically contradicts Appellant’s contention as to what the scientific expectation was at the time of Appellant’s invention. And for this reason, we disagree with Appellant’s characterization of Example 8 of Leigh as being incomplete for failure to describe the use of solvents and surfactants and that “the examples of Leigh confirm that [solvents and surfactants] are not optional at all, as they are used in every example except the incomplete Example 8.” (Reply Br. 3.) Appeal 2020-005497 Application 15/593,586 13 In addition, Leigh teaches, even apart from its own surprising discovery, among the known “manufacturing procedures to associate the lipophilic drug with the lipids [of a liposome] . . . included high shear and/or high pressure homgenisation” aside from “controlled organic solvent dilution, [and] cross flow filtration to produce aqueous liposomal suspensions containing the drug.” (Leigh ¶ 6.) We note further that WO ’358 confirms that it was known that homogenization can be used to associate lipophilic drugs with phospholipid liposomes in an aqueous solution. (WO ’358 ¶ 114.) In light of the foregoing, the fact that Example 8 of Leigh does not provide a specific protocol for combining a lyophilized lipophilic drug with an aqueous dispersion to obtain a liposome having the lipophilic drug in association with the membrane lipid does not persuade us that Leigh in combination with WO ’358 does not render obvious the claimed process wherein no solvent or surfactant is used in associating a lipophilic therapeutic agent with a lipid of a liposome. Moreover, we conclude that the addition of a homogenization step would have been obvious from the teachings of Leigh and WO ’358 to ensure efficiency of loading into the membrane over Leigh’s expected 80% efficiency by the “instant partition loading.” (Leigh ¶ 36). Moreover, the fact that Example 8 of Leigh does not describe a liposome having the claimed liposome size and lamellarity (Appeal Br. 8) does not persuade us that these features are not rendered obvious from the teachings of the relied upon references. Leigh teaches that unilamellar vesicles are known lipid particles that can be loaded by instant partition loading. (Leigh ¶ 56.) Although Leigh specifically teaches using such Appeal 2020-005497 Application 15/593,586 14 vesicles with a lipophilic drug that is dissolved in PEG400/ethanol (id. ¶ 54), Leigh does not teach this to be the only process in which such vesicles can be used. Leigh, instead, particularly notes that where the low water soluble compound to be associated with the lipid of the vesicle is lyophilized, the compound does not need to be in a container that includes a solvent or surfactant in order to take advantage of instant partition loading. (Id. ¶ 33.) Leigh notes that use of excipients may “improve solubility and the loading of the lipids” but they are not necessary. (Id. ¶ 49.) And, Leigh teaches that the aqueous suspension of discrete lipid particles that may be used, taking advantage of this surprising discovery with respect to instant partition loading, “most preferably” has particle sizes of below 100 nm. (Id. ¶ 35.) Thus, we agree with the Examiner that the prior art renders obvious the claimed process wherein no solvent or surfactant is used in associating a lipophilic therapeutic agent with a lipid of a liposome where the liposomes are unilamellar and have an average size less than about 100 nm. Moreover, regarding Appellant’s position that WO ’358 teaches a method that requires the presence of a surfactant, for example, cholesteryl sulfate (Appeal Br. 9, 12), we disagree. “It is well settled that a prior art reference is relevant for all that it teaches to those of ordinary skill in the art.” In re Fritch, 972 F.2d 1260, 1264 (Fed. Cir. 1992). Although cholesteryl sulfate is used in every example where the liposome was homogenized with the lipophilic drug in WO ’358, WO ’358 discloses that cholesteryl sulfate is just one of a number of other lipids that may be included, which list includes just using cholesterol itself. (WO ’358 ¶ 21.) Moreover, WO ’358 teaches that formulations of amphotericin B incorporated into unilamellar liposomes formed from soy Appeal 2020-005497 Application 15/593,586 15 phosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol are known and that use of cholesteryl sulfate simply reduces the toxicity of amphotericin B on use of the liposome by reducing hemolysis of erythrocytes and binding to plasma protein. (WO ’358 ¶¶ 78, 80.) Furthermore, we agree with the Examiner that it was known in the art that cholesterol in combination with phospholipids in forming liposomes was known to provide structural support to the liposome. (Hope ¶ 504.) Thus, we conclude, like the Examiner, that WO ’358’s teaching regarding the use of cholesterol lipids in the liposome composition is for its use in structural support of a liposome that may be subject to homogenization, and that a surfactant type cholesterol, therefore, is not required. That using cholesteryl sulfate would not have been understood by one of ordinary skill in the art to teach at the time of Appellant’s invention to be necessary to incorporate a lipophilic into drug into the lipid bilayer of the liposome is also supported by Leigh’s teaching just discussed: namely that, upon mixing, lipophilic compounds that have a low solubility in aqueous media with liposomes suspensions in aqueous media “spontaneously and instantaneously” form molecular associates between the lipophilic compound and liposomes due to preferential partitioning of the lipophilic compound into the lipid of the aqueous suspension. (Leigh ¶¶ 22, 33.) 4 Hope states: In membranes composed of unsaturated phospholipids, the presence of cholesterol restricts acyl chain motion and increases membrane thickness. On the other hand, the interaction of cholesterol with saturated phospholipids prevents the formation of the gel state and tends to eliminate the gel to liquid crystalline phase transition[.] (Hope ¶ 50.) Appeal 2020-005497 Application 15/593,586 16 Consequently, we agree with the Examiner that the teachings of WO ’358 and Leigh in combination would have made obvious the process recited in Appellant’s claim 1. Appellant does not separately argue the patentability of claims 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51, and thus, they fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). We affirm the Examiner’s rejection of claims 1, 4–8, 11–16, 18, 20–31, 33–37, 40–45, 47, and 49–51 as being unpatentable over Leigh in combination with WO ’358 and claims 1, 4–8, 11–31, 33–37, and 40–54 as being unpatentable over WO ’358 in combination with Daftary and Leigh. We need not, and do not address the Examiner’s rejection of claims 1, 4–8, 11–16, 18, and 20–24 as obvious over Leigh in combination with Desai and Haas, because these came claims have also been rejected as obvious over the combination of Leigh and WO ’358 alone, or also in combination with Daftary, which, as just discussed, are rejections that we affirm. II. Obviousness Rejections Involving Independent Claim 25 Appellant’s claim 25 differs from claim 1 in that the hydrophobic therapeutic agent is said to be dissolved in a liquid-solvent-containing medium, but requires that the addition of a hydrophobic agent to a liposome suspension and homogenization take place in the absence of a surfactant. The Examiner makes two different rejections of claims 25–31, 33–37, 40–45, 47, and 49–51, but both rely on the teachings of Hope. According to the Examiner, Hope teaches loading drugs, including hydrophobic drugs, into preformed liposomes where ethanol and solvents “such as DMSO below a certain amount” are used to increase the permeability of the liposome without vesicular collapse. (Non-Final Action Appeal 2020-005497 Application 15/593,586 17 8, 9.) The Examiner concludes that it would have been obvious to load the liposomes of WO ’358 after the liposomes are formed “since Hope teaches that preformed liposomes can be loaded with an active agent.” (Id. at 8.) The Examiner also finds that it would have been obvious to lyophilize the Hope liposomes loaded with drug for storage purposes as taught by Desai and Haas. (Id. at 9.) Appellant argues that the Examiner’s rejections of claim 25 involving Hope are in error because “Hope discloses merely the entrapment of only water-soluble drugs using organic solvent to destabilize the membrane, not to deliver a hydrophobic drug.” (Appeal Br. 12.) According to Appellant, Hope does not teach dissolving drugs in organic solvent, but rather “discloses a drug trapping method in which organic solvent is added to liposomes to permeabilize them, following which the organic solvent is removed, allowing the liposomes to reseal and entrap a solute at the same concentration at which it exists in the suspension.” (Id. at 10.) Appellant argues that “it is doubtful that Hope’s method can work with a hydrophobic drug, because it requires use of an aqueous solution of the drug, which merely becomes entrapped in the liposomal lumen, not intercalated within the lipid bilayer as in Appellant’s method.” (Id. at 11.) We do not find Appellant’s argument persuasive. Hope teaches in the abstract that loading of preformed liposomes of solutes that include “both small nonpolar molecules and larger species, such as proteins and carbohydrates.” (Hope Abstr.) Indeed, Hope indicates that the molecular characteristic of the drug is irrelevant to whether or not the drug can be loaded, stating: Appeal 2020-005497 Application 15/593,586 18 Generally, the loading of all drugs that can cross the vesicle bilayer in the presence of up to 30% ethanol are contemplated by this invention. Such drugs can be readily identified by encapsulating the drug of interest and then adding ethanol to see if the drug is released from the vesicle. One will recognize that this method of loading and/or release is therefore independent of any particular molecular characteristic of the drug (e.g., charge, molecular weight, etc.). (Id. ¶ 64.) Moreover, Hope also teaches with respect to the solvent addition that the molecule to be loaded can be suspended in organic solvent and added to the liposome instead of the liposome being suspended in an organic solvent with the molecule to be loaded added afterward. (Hope ¶ 62.) Hope specifically states “the order of addition is unimportant.” (Id.) Finally, Hope teaches that “[t]he alcohol temporarily enhances the permeability of the vesicles, without substantially altering or changing their size” and that the liposomal membrane retains its “structural integrity” (Hope ¶ 46.) Hope explains that the solvent is generally a polar solvent. (Id. ¶ 52.) In the face of the foregoing teachings in Hope, Appellant’s argument that “it is doubtful that Hope’s method can work” (Appeal Br. 11) is not supported by the evidence of record and is unpersuasive. “Attorney argument is not evidence.” Icon Health & Fitness v. Strava, 849 F.3d 1034, 1043 (Fed. Cir. 2017) (citing Gemtron Corp. v. Saint-Gobain Corp., 572 F.3d 1371, 1380 (Fed. Cir. 2009) (“[U]nsworn attorney argument . . . is not evidence and cannot rebut . . . other admitted evidence . . . .”); see also Manual of Patent Examining Procedure § 2145 (9th ed. Nov. 2015) (“Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection.”). Appeal 2020-005497 Application 15/593,586 19 Furthermore, Leigh teaches that it was known at the time of the invention, that where a lipophilic compound is added to a preformed liposomal particles, either as a particulate or in a hydrophilic medium such as ethanol, the compound partitions preferentially into the lipid to form molecular associations. (Leigh ¶¶ 32, 33.) Consequently, Leigh supports a conclusion that the use of a solvent as in Hope, which would assist in permeabilizing the liposome membrane, thus facilitating entry of the lipophilic compound into the lipid bilayer would also result in the instantaneous and spontaneous partition loading of a lipophilic compound into molecular association with the lipid of the liposome membrane. For the foregoing reasons, we affirm the Examiner’s rejection of claim 25 as being unpatentable over Hope, Desai, and Hass, or Hope, WO ’358, Leigh, and Daftary. Appellant does not separately argue the patentability of claims 26–31, 33–37, 40–45, 47, and 49–51, and thus, they fall with claim 25. 37 C.F.R. § 41.37(c)(1)(iv). III. Non-statutory Double Patenting Appellant does not contest the Examiner’s rejection of the claims for non-statutory double patenting over claims 1–5 of U.S. Patent No. 8,591,942. (Appeal Br. 7.) Appellant also has not filed a terminal disclaimer to obviate the rejection, and we therefore, summarily affirm the Examiner’s rejection. Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008) (“When the appellant fails to contest a ground of rejection to the Board, . . . the Board may treat any argument with respect to that ground of rejection as waived.”). Appeal 2020-005497 Application 15/593,586 20 DECISION SUMMARY Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 4–8, 11– 16, 18, 20– 31, 33–37, 40–45, 47, 49–51 103(a) Leigh, WO’358 1, 4–8, 11– 16, 18, 20– 31, 33–37, 40–45, 47, 49–51 1, 4–8, 11– 31, 33–37, 40–54 103(a) WO’358, Daftary, Leigh 1, 4–8, 11– 31, 33–37, 40–45, 47, 49–51 25–31, 33– 37, 40–45, 47, 49–51 103(a) WO’358, Daftary, Leigh, Hope 25–31, 33– 37, 40–45, 47, 49–51 25–31, 33– 37, 40–45, 47, 49–51 103(a) Hope, Desai, Hass 25–31, 33– 37, 40–45, 47, 49–51 1, 4–8, 11– 16, 18, 20– 31, 33–37, 40–45, 47, 49–51 Non-statutory Double Patenting 1, 4–8, 11– 16, 18, 20– 31, 33–37, 40–45, 47, 49–51 Overall Outcome 1, 4–8, 11– 31, 33–37, 40–45, 47, 49–51 TIME PERIOD FOR RESPONSE 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 Copy with citationCopy as parenthetical citation