DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims included in prosecution are claims 1-5, 8, 10, 15, and 17-22.
Previous Rejections
Applicants' arguments, filed 12/29/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claim(s) 1-5, 8, 10, 15, and 20-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer et al. (US 2018/0263909, Sep. 20, 2018) (hereinafter Bilgicer) in view of Chang et al. (US 2019/0194281, Jun. 27, 2019) (hereinafter Chang) and Wamhoff et al. (US 2015/0111240, Apr. 23, 2015) (hereinafter Wamhoff).
Bilgicer teaches pharmaceutical compositions comprising liposomes that contain two or more anticancer drugs (Abstract). The liposome comprises: a) a phospholipid; b) a pegylated lipid; c) an aqueous core (satisfies claim 20); and d) at least two different drug components, wherein the drug components comprise a covalently-linked drug conjugated lipid, an encapsulated drug, or a combination thereof, and wherein the drug components are anticancer drugs (satisfies components c. of claim 1) (¶ [0008-0012]). The diameter of the liposome is about 5 nm to about 200 nm (satisfies claim 15) (¶ [0013]). The drug combinations may include a proteasome inhibitor and a histone deacetylase inhibitor (HDAC inhibitor) wherein the two different drug components are present in a synergistic ratio (¶ [0014]). Suitable proteasome inhibitors for use include bortezomib (satisfies treatment compound of claim 3-4). Suitable HDAC inhibitor include vorinostat (¶ [0015]). Suitable pegylated lipids include DSPE-PEG2000 (¶ [0018]). In one embodiment, the liposome comprises at least one encapsulated drug component and the encapsulated drug component is localized to the aqueous core. The encapsulated drug can also be located in the lipid bilayer of the liposome. Other drugs and various drug conjugates may also be located in the lipid bilayer and/or they can be localized, at least in part, to the aqueous core (¶ [0019]). The liposome can be administered as a composition for the treatment of multiple myeloma (satisfies composition of claim 1) (¶ [0027]). The liposome can comprise a combination of one or more phospholipids, an optional lipid that is not a phospholipid, such as cholesterol, pegylated lipids, or a combination thereof (¶ [0073]). The addition of pegylated lipids to the liposomal nanoparticle significantly reduces toxicity and the potential for rejection by the host's immune system (¶ [0087]). The composition may be in the form of a capsule wherein the capsule may include a liquid carrier for the composition (satisfies claim 21) (¶ [0095]). A loading efficiency of more than 95% was achieved for both drugs (satisfies claim 5) (¶ [0119]).
Bilgicer differs from the instant claims insofar as not disclosing wherein the liposome contains a targeting moiety such as PSGL-1 coupled to the outer surface.
However, Chang teaches the delivery of an agent to autophagic and/or apoptotic cells and tissues through a vesicle with an engineered protein expressed on or conjugated to the surface thereof (¶ [0001]). The invention comprises one or more lectins or a fragment thereof expressed or conjugated to the surface of the vesicle and optionally an agent (¶ [0005]). Particular embodiments of the vesicle include liposome and micelle (¶ [0006]). Suitable lectins or fragments thereof include P-selectin-ligand-1 (PSGL-1) (¶ [0007]). Suitable agents to be delivered include antitumor drugs (¶ [0012]). The delivery of an agent or a therapeutic agent with the vesicle to apoptotic cells is directed to a disease associated with apoptosis alteration such as cancer (¶ [0075]).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified Bilgicer’s liposome to include a targeting moiety such as PSGL-1 motivated by the desire to achieve a liposome that specifically targets cancer affected cells in order to directly deliver antitumor actives to said affected cells as taught by Chang.
The combined teachings of Bilgicer and Chang do not disclose wherein the composition comprises a BMME-disrupting agent such as Y27632.
However, Wamhoff discloses that suitable anticancer agents include proteasome inhibitors such as bortezomib, HDAC inhibitors such as vorinostat, rho kinase inhibitors such Y27632, and combinations thereof (¶ [0242]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Bilgicer discloses wherein the liposome may contain another anticancer agent in addition to bortezomib. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have formulated the composition of Bilgicer in view Chang to comprise Y27632, since it is a known anticancer agent as taught by Wamhoff.
Alternatively, it is obvious to replace one component for another equivalent component if it is recognized in the art that the two components are equivalent and is not based on the Applicant disclosure. See MPEP 2144.06. Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have formulated Bilgicer’s composition to comprise Y27632 in place of vorinostat because they are taught as equivalents by Wamhoff.
Regarding the encapsulation efficiency recited in instant claim 10 (i.e., about 40%-60%), in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, Bilgicer’s liposome achieved more than 95% loading efficiency for both drugs. Accordingly, because the encapsulation efficiency recited in the instant claims lie inside the loading efficiency disclosed by Bilgicer, the loading efficiency disclosed by Bilgicer meets the instantly recited limitations.
Regarding the dosage recited in instant claim 22, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). As discussed above, Bilgicer’s liposomes are therapeutic where they contain anticancer agents, which makes their dosage a result effective variable, since dosage directly impacts the therapeutic effect. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed dosage of 2 mg/mL to yield the desired anticancer (i.e., therapeutic) effect.
Therefore, the combined teachings of Bilgicer, Chang, and Wamhoff render obvious claims 1-5, 8, 10, 15, and 20-22.
2. Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer et al. (US 2018/0263909, Sep. 20, 2018) (hereinafter Bilgicer) in view of Chang et al. (US 2019/0194281, Jun. 27, 2019) (hereinafter Chang) and Wamhoff et al. (US 2015/0111240, Apr. 23, 2015) (hereinafter Wamhoff) and further in view of Vogel et al. (Scientific Reports | 7: 17479, Dec. 12, 2017) (hereinafter Vogel).
The teachings of Bilgicer and Chang are discussed above.
The combined teachings of Bilgicer and Chang do not disclose wherein the zeta potential of the liposome is at least 28 mV.
However, Vogel discloses that zeta potential, which is indicative of the particle surface charge, is an important and widely used characterization method of nanometer-sized objects in pharmaceuticals and liposomes. Zeta potential values of typically ±30 mV are representative of stabilized particles (Introduction, Par. 2).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified Bilgicer’s liposome to have a zeta value of around 30 mV motivated by the desire to achieve a stable liposome as taught by Vogel.
Therefore, the combined teachings of Bilgicer, Chang, Wamhoff, and Vogel render obvious claim 17.
3. Claim(s) 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer et al. (US 2018/0263909, Sep. 20, 2018) (hereinafter Bilgicer) in view of Chang et al. (US 2019/0194281, Jun. 27, 2019) (hereinafter Chang) and Wamhoff et al. (US 2015/0111240, Apr. 23, 2015) (hereinafter Wamhoff) and further in view of Unger et al. (US 2016/0000943, Jan. 7, 2016) (hereinafter Unger).
The teachings of Bilgicer and Chang are discussed above.
While the combined teachings of Bilgicer and Chang disclose the use of cholesterol and DSPE-PEG2000, they do not disclose wherein the composition comprises DPPC and DSPE-PEG(2000)-succinyl.
However, Unger teaches a phospholipid composition (¶ [0002]). Suitable phospholipids for use include dipalmitoylphosphatidylcholine or DPPC (¶ [0028]). Suitable pegylated lipids which may be employed include DSPE-PEG(2000) Succinyl (¶ [0054]). In certain examples, the composition may be used to target cancer cells (¶ [0094]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Bilgicer discloses wherein the liposome may contain phospholipids and pegylated lipids. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have formulated the composition of Bilgicer to comprise DPPC and DSPE-PEG(2000) Succinyl, since they are known phospholipids and pegylated lipids used in compositions to treat cancer as taught by Unger.
Regarding the ratio recited in instant claim 19, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). As discussed above, the lipid bilayer of Bilgicer’s liposome is formed from lipids, phospholipids, and pegylated lipids, which makes ratios thereof a result effective variable, since the lipid bilayer composition would directly impact the bilayers physical properties. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed ratio of 6:3:0.5:0.5 to yield the desired lipid bilayer composition.
Therefore, the combined teachings of Bilgicer, Chang, Wamhoff, and Unger render obvious claims 18-19.
Response to Arguments
Regarding Applicant’s arguments that Y27632 is “NOT an anticancer agent”, the Examiner submits that a reference is relied upon for all it teaches and suggests, even non-preferred embodiments. See MPEP § 2141.02 (VI). As discussed above, Wamhoff explicitly discloses that Y27632, a rho kinase inhibitor, is suitable “anti-cancer agent”. Bilgicer discloses wherein the encapsulated drug components are anticancer drugs. Accordingly, since references are relied upon for all they teach and suggest, where Wamhoff discloses that Y27632 is a suitable anti-cancer agent and Bilgicer requires such agents, it would have been obvious for one of ordinary skill in the art to have utilized Y27632 in the composition of Bilgicer as explained above.
Applicant’s alleged finding that Y27632 is “NOT an anticancer agent” because of the data in Fig. 6C is merely a showing that Y27632 is possibly less effective on its own than bortezomib on its own or both actives in combination. However, variation in effectiveness between actives is known and expected. It would also be reasonably expected for two known actives, when used in combination, to yield a more pronounced additive effect when compared to utilizing each individual active on its own. The mere demonstration by Applicant that Y27632 is potentially less effective on its own on MM, does not negate the fact that Wamhoff does unambiguously disclose that Y27632 is considered a “anti-cancer agent” within the four corners of its disclosure.
Further, Example 10 which Applicant points to is related to evaluating the loading of the therapeutic compound and the BMME-disrupting agent into the targeted liposomes and does not discuss the effectiveness of either compound nor does it appear to make any mention of Fig. 6C.
Regarding Applicant’s argument that “Y27632 and vorinostat are NOT equivalents because Y27832 is NOT an anticancer agent”, the Examiner submits that assuming, purely arguendo, that one of ordinary skill in the art would not be led by the combined teachings of Bilgicer and Wamhoff to the finding that Y27632 is an “anticancer agent”, as discussed above, Wamhoff discloses bortezomib, vorinostat, and Y27632 as equivalents. As discussed above, it is obvious to replace one component for another equivalent component if it is recognized in the art that the two components are equivalent and is not based on the Applicant disclosure. See MPEP 2144.06. Accordingly, it would have been obvious for one of ordinary skill in the art, to have formulated Bilgicer’s composition to comprise Y27632 in place of vorinostat because they are taught as equivalents by Wamhoff, regardless of the nomenclature or designation applied to those components. In other words, this replacement logically follows as a result of their equivalence being established by the art, not as a result of how the reference labels them.
In light of the foregoing, the Examiner does not find Applicant’s arguments to be persuasive and the rejection is maintained.
Conclusion
Claims 1-5, 8, 10, 15, and 17-22 are rejected.
Claims 23-27 are withdrawn.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Abdulrahman Abbas whose telephone number is (571)270-0878. The examiner can normally be reached M-F: 8:30 - 5:30.
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/A.A./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612