DETAILED ACTION
Applicants’ arguments, filed 23 September 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Interpretation
Claim 1 recites a sphingophospholipid. The examiner understands sphingomyelin to be a sphingophospholipid. See the instant specification on page 2 lines 24-28.
Regarding claims 1 and 4, the examiner notes that cholesterol reads on the required surfactant. The examiner does not take a position as to whether cholesterol is a surfactant based upon the ordinary definition of the term “surfactant.” Nevertheless, applicant is entitled to be their own lexicographer and may rebut the presumption that claim terms are to be given their ordinary and customary meaning by clearly setting forth a definition of the term that is different from its ordinary and customary meaning(s) in the specification at the relevant time. See MPEP 2111.01(IV)(A). In this case, the examiner understands that claim 4 has defined the term “surfactant” to include cholesterol, regardless of whether the ordinary scope of the term “surfactant” would have included cholesterol. The examiner’s search will focus on cases wherein cholesterol is the surfactant as this is the subject matter of claim 4.
Regarding claims 6-7, the examiner notes that the instant claims are drawn to a pre-liposomal lyophilizate. The skilled artisan would have expected a pre-liposomal lyophilizate to have been a solid product. While claim 1 recites liposomes formed by reconstitution with an aqueous solution, the examiner takes the position that the use of this aqueous solution and the presence of liposomes is an intended use of the pre-liposomal composition. As such, a pre-liposomal lyophilizate that is not present in the presence of the aqueous solution but would form liposomes if added to an aqueous solution is understood to read on the invention of claims 6-7. In a similar vein, the combination of the pre-liposomal lyophilizate with an aqueous solution having a specific concentration of active agent, as recited in claim 7, is understood to be an intended use of the composition. Prior art that teaches a pre-liposomal lyophilizate but does not teach an aqueous solution comprising the required active agent in the required concentration is understood to meet the claimed limitation provided that the pre-liposomal lyophilizate could be hydrated to form a liposome in the presence of an aqueous solution comprising active agent in the recited concentrations.
Note Regarding PD-1 Immune Checkpoint Inhibitors
The instant claims have been amended to require a PD-1 immune checkpoint inhibitor. The examiner has cited Yamada et al. (US 2019/0376146 A1), page 6, Table 1, which provides examples of PD-1 immune checkpoint inhibitors and is reproduced below.
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The skilled artisan would have understood that the anti PD-1 antibodies are hydrophilic because antibodies are water-soluble proteins.
Claim Rejections - 35 USC § 103 – Obviousness
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.
Claim(s) 1, 3-7, 11-12, 22, and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. (US 2012/0128762 A1) in view of Giannakis et al. (WO 2019/089740 A1).
Chancellor et al. (hereafter referred to as Chancellor) is drawn to sphingomyelin liposomes for instillation, as of Chancellor, title and abstract. While Chancellor teaches the treatment of interstitial cystitis, as of Chancellor, abstract, Chancellor also teaches administration of anticancer agents to the bladder, as of the abstract of Chancellor, indicating that Chancellor intends to treat bladder cancer.
As to claim 1, the claim requires a pre-liposomal lyophilizate. Chancellor teaches a dry lyophilized powder in paragraph 0077. Chancellor suggests adding water or saline to reconstitute prior to administration as of paragraph 0077. Elsewhere in the reference, Chancellor provides teachings regarding the liposomes themselves.
Chancellor does not teach an anti-PD1 immune checkpoint inhibitor.
Giannakis et al. (hereafter referred to as Giannakis) is drawn to methods for predicting a response to immune checkpoint therapy, as of Giannakis, title and abstract. Giannakis teaches that the FDA has approved nivolumab for primary or metastatic urothelial carcinoma, which is the most common form of bladder cancer, as of Giannakis, page 21 lines 26-28.
Giannakis does not teach the required liposome or pre-liposomal lyophilizate.
It would have been prima facie obvious for one of ordinary skill in the art to have combined the nivolumab of Giannakis with the composition of Chancellor. Chancellor is drawn to a liposomal composition or pre-liposomal lyophilizate intended for instillation into the bladder. Chancellor also suggests the inclusion of an anti-cancer agent. Giannakis teaches that nivolumab has been approved by the FDA for the treatment of bladder cancer. As such, the skilled artisan would have been motivated to have included the nivolumab of Giannakis in the composition of Chancellor for predictable treatment of bladder cancer with a reasonable expectation of success. Generally, it is prima facie obvious to select a known material (e.g. nivolumab, as of Giannakis) for incorporation into a composition (e.g. that of Chancellor), based on its recognized suitability for its intended use (as an anti-cancer agent against bladder cancer). See MPEP 2144.07.
As to claim 1, the claim requires that the liposome have a shell comprising a sphingophospholipid and a surfactant. Chancellor teaches sphingomyelin and cholesterol together, as of paragraph 0181. The skilled artisan would have understood that sphingomyelin reads on the required sphingophospholipid and cholesterol reads on the required surfactant.
As to claim 1, the claim requires an aqueous core. Chancellor teaches this exact language on paragraph 0164. Regardless, the skilled artisan would have been aware that liposomes have a lipid bilayer and aqueous core.
As to claim 1, the claim requires a hydrophilic therapeutic, prophylactic, or diagnostic agent. Chancellor teaches bioactive agents as of paragraph 0083. These bioactive agents include nucleic acids, polypeptide, or antibodies, all of which are hydrophilic. Chancellor teaches encapsulation, including of antisense RNA, as of paragraph 0148. The skilled artisan would have expected that in view of the principle of like-dissolves-like, a hydrophilic therapeutic agent would have been present in the aqueous core upon encapsulation (whereas a hydrophobic therapeutic agent would have been present in the hydrophobic bilayer).
As to claim 1, Chancellor appears to teach all of the claimed requirements, albeit not in the same embodiment. While the prior art teaches all of the claimed components, the prior art is not anticipatory insofar as these components must be selected from various lists/locations in the prior art reference. It would have been prima facie obvious; however, to have selected the recited components from various lists/locations in the prior art reference and to have combined them together. This is because such a modification would have represented nothing more than the predictable use of prior art components according to their established functions. Combining separate prior art components (from a single prior art reference) according to known methods to yield predictable results is prima facie obvious. See MPEP 2143, Exemplary Rationale A.
As to claim 3, Chancellor teaches sphingomyelin, as of paragraph 0181.
As to claim 4, Chancellor teaches cholesterol, as of paragraph 0181.
As to claim 5, Chancellor teaches a 2:1 molar ratio of sphingomyelin to cholesterol in paragraph 0181; this is a 1:2 molar ratio of surfactant to sphingophospholipid. The examiner presents the following conversion to convert this to a mass ratio
1
m
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2
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p
m
×
386.6
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m
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×
1
m
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p
m
646
t
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830
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=
a
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t
23
t
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29
%
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a
s
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m
The amount of cholesterol appears to be higher in Chancellor than what is required by the instant claims. Nevertheless, 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). In this case, the general conditions of a sphingomyelin/cholesterol liposome have been taught by Chancellor, along with ratios of these ingredients. As such, it would not have been inventive to have discovered the optimum or workable ranges of these ingredients via routine experimentation.
As to claim 6, Chancellor teaches the following, as of paragraph 0077, reproduced below.
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The sterile water or saline of paragraph 0077 of Chancellor is understood to read on the additional limitations of claim 6.
As to claim 7, the skilled artisan would have expected that if the pre-liposomal composition of Chancellor were combined with an aqueous solution comprising an active agent in the recited concentration, then liposomes would be formed. See the section above entitled “Claim Interpretation” for a description of how claim 7 is to be interpreted.
As to claim 11, Chancellor teaches ethanol as a pharmaceutically suitable excipient, as of paragraph 0076.
As to claim 12, this claim requires the same subject matter as claim 1 except reciting liposomes rather than a pre-liposomal lyophilizate. Chancellor teaches both liposomes and a pre-liposomal lyophilizate. As such, Chancellor is understood to render claim 12 obvious for essentially the same reason that Chancellor renders claim 1 obvious.
As to claim 22, Chancellor teaches intravesical instillation as of at least paragraph 0060. The examiner understands this to read on direct administration to the bladder lumen.
As to claim 24, Chancellor teaches a liposome size range of about 0.2 to 0.4 microns in paragraph 0095 of Chancellor; this is within the claimed range.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. (US 2012/0128762 A1) in view of Giannakis et al. (WO 2019/089740 A1), the combination further in view of Patel et al. (Journal of Pharmaceutical Sciences, Vol. 106, 2017, pages 1706-1712).
Chancellor et al. (hereafter referred to as Chancellor) is drawn to sphingomyelin liposomes for instillation for treatment of interstitial cystitis, as well as a pre-liposomal lyophilizate thereof. Giannakis teaches nivolumab as an anti-cancer agent for bladder cancer. See the rejection above over Chancellor in view of Giannakis by themselves.
Chancellor does not teach that the pre-liposomal lyophilizate is in the form of a cake.
Patel et al. (hereafter referred to as Patel) is drawn to lyophilized drug products, as of Patel, page 1706, title and abstract. Patel teaches that a cake appearance is an important goal during the design of a lyophilized drug product, as of Patel, page 1706, abstract.
Patel does not teach a liposomal product.
It would have been prima facie obvious for one of ordinary skill in the art to have formulated the lyophilized composition of Chancellor to have been in the form of a cake. Chancellor teaches a lyophilized product, but is silent as to the form and/or appearance of the lyophilized product. Patel teaches that lyophilized products in the form of a cake is beneficial and desirable. As such, the skilled artisan would have been motivated to have formulated the lyophilized composition of Chancellor to have been in the form of a cake in order to have predictably provided beneficial pharmaceutical quality with a reasonable expectation of success.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. (US 2012/0128762 A1) in view of Giannakis et al. (WO 2019/089740 A1), the combination further in view of Kaufmann et al. (US 2016/0263031 A1).
Chancellor et al. (hereafter referred to as Chancellor) is drawn to sphingomyelin liposomes for instillation for treatment of interstitial cystitis, as well as a pre-liposomal lyophilizate thereof. Giannakis teaches nivolumab as an anti-cancer agent for bladder cancer. See the rejection above over Chancellor in view of Giannakis by themselves.
For the purposes of this rejection, purely en arguendo and for the purposes of this ground of rejection only, the examiner takes the position that Chancellor does not teach the drug concentration.
Kaufmann et al. (hereafter referred to as Kaufmann) is drawn to a metastable liposome for delivery to a tissue such as the lumen of the bladder, as of Kaufmann, title and abstract. Although Kaufmann teaches hydrophobic drugs in the abstract, the examiner notes that Kaufmann teaches the delivery of various nucleic acids in paragraph 0076. The skilled artisan would have recognized these nucleic acids as hydrophilic. Kaufmann teaches concentration of active agents in mg/mL in paragraph 0104, including a concentration of 0.05 mg/mL to 5 mg/mL, as of paragraph 0104.
Kaufmann differs from the claimed invention because the examples of Kaufmann do not appear to include cholesterol (i.e. the surfactant required by claim 4); in contrast, Example 3 of Kaufmann includes only sphingomyelin. (While Kaufmann teaches cholesterol, it is in a list of agents, and not in the examples; as such, Kaufmann is not anticipatory).
It would have been prima facie obvious for one of ordinary skill in the art to have modified the composition of Chancellor to have included active agents in the composition taught by Kaufmann. Chancellor is drawn to a liposome composition for the delivery of active agents. However, Chancellor is silent as to the concentration of active agents in mg/mL. Kaufmann teaches that active agents may be present in a concentration of 0.05 mg/mL to 5 mg/mL. As such, the skilled artisan would have been motivated to have modified the composition of Chancellor to have included active agents in the concentrations taught by Kaufmann for predictable delivery of said active agents to the bladder in a patient suffering from interstitial cystitis with a reasonable expectation of success.
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chancellor et al. (US 2012/0128762 A1) in view of Giannakis et al. (WO 2019/089740 A1), the combination further in view of Harris et al. (US 2004/0157307 A1).
Chancellor et al. (hereafter referred to as Chancellor) is drawn to sphingomyelin liposomes for instillation for treatment of interstitial cystitis, as well as a pre-liposomal lyophilizate thereof. Giannakis teaches nivolumab as an anti-cancer agent for bladder cancer. See the rejection above over Chancellor in view of Giannakis by themselves.
For the purposes of this rejection, the examiner takes the position that there is insufficient evidence to determine that the composition of Chancellor would have been stable to settling for the recited period of time of at least 1 day.
Harris et al. (hereafter referred to as Harris) is drawn to vaccines. Although the main focus of Harris is vaccines, the examiner notes that Harris teaches the following as of paragraph 0201, which is reproduced below.
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As such, Harris teaches sphingomyelin liposomes, and teaches the use of negatively charged phospholipids to prevent aggregation.
Harris differs from the claimed invention because Harris does not teach cholesterol.
It would have been prima facie obvious for the skilled artisan to have modified the liposome of Chancellor to have included a negatively charged lipid. Chancellor is drawn to a sphingomyelin liposome. Chancellor is silent as to the stability of the liposome toward aggregation. However, Harris teaches that the inclusion of lipids with a negative charge can prevent aggregation. As such, the skilled artisan would have been motivated to have modified the liposome of Chancellor to have included the negatively charged lipids of Harris in order to have predictably prevented aggregation with a reasonable expectation of success, and to have predictably enabled stability toward aggregation for at least one day with a reasonable expectation of success.
Response to Arguments
Applicant has presented arguments regarding the previously applied rejection, as of applicant’s response on 23 September 2025 (hereafter referred to as applicant’s response). These arguments are addressed below.
In applicant’s response, pages 9-11, applicant argues that Chancellor as well as the other references relied upon fail to teach the required anti-PD-1 immune checkpoint inhibitor. The examiner does not dispute this, but takes the position that the combination of Chancellor with Giannakis teaches the required immune checkpoint inhibitor. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See MPEP 2145(IV).
Relevant Patents – No Double Patenting
As relevant references, the examiner cites US patent 10,639,278, 11,357,725, and 12,138,345. The examiner notes that these patents have common inventors with the instant application. The claims of both patents appear to be drawn to sphingomyelin liposomes.
The examiner reviewed the claims of these patents, and has made the decision not to reject the instant claims over the claims of US Patents 10,639,278, 11,357,725, and 12,138,345 on the grounds of non-statutory double patenting. This is because the claims of both patents appear to be drawn to a hydrophobic agent rather than a hydrophilic agent. In view of this deficiency, the examiner has not rejected the instant claims over the claims of US Patents 10,639,278, 11,357,725, and 12,138,345 on the grounds of non-statutory double patenting.
The instant claims were previously rejected on the grounds of non-statutory double patenting over the claims of US Patent 11,607,386. This rejection has been withdrawn. This is because the claims of the ‘386 patent do not recite at least one anti PD-1 immune checkpoint inhibitor.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612