DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed September 22, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Status
Claims 1, 5, 11, 13, and 20 have been amended.
Claims 1 – 24 are examined here-in.
Claim Rejections - 35 USC § 102 (Maintained)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 4-10, 12-14, 16, 17, 19 - 21, 23, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Phillips ("Rhenium=186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma" Neuro-Oncology 2012, of record).
Phillips teaches a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1). Phillip’s liposomes were radiolabeled with rhenium-186 BMEDA (N,N-bis(2-mercaptoethyl)-N’,N’-diethylenediamine) (page 418 column 1).
Phillips’ method for administering 186Re-labeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1) anticipates claim 1 of the instant application.
Phillips teaches that 2 mL liposomes with 60 mM total lipid were labeled with rhenium-186 BMEDA containing 115 mCi (page 418 column 1), then 25 µL were injected (page 420 column 2). With consideration of the injection volume (25 µL) being 1/80th of the initial liposome formulation volume (2 mL), approximately 1.4 mCi is present in the 25 µL fraction. According to MPEP 2131.03(i), a specific example in the prior art which is within the claimed range anticipates the range, therefore, Phillips’ teaching of 1.4 mCi anticipates the instantly claimed range of 1 to 250 mCi as recited in instant claim 1. Notably, the instant specification states that the term “delivered” is interchangeable with the term “administered” (paragraph 0059), therefore the administration of 1.4 mCi in 25 µL reads on the limitation of “delivered to” in claim 1.
Phillips’ use of rhenium-186 BMEDA anticipates claims 2 and 4 of the instant application.
Phillips teaches that rhenium-186 BMEDA was loaded into liposomes via an ammonium pH gradient (page 418), anticipating claim 5 of the instant application which recites the compound is incorporated into the liposome.
Phillips’ liposomes were composed of distearoylphosphatidylcholine and cholesterol (page 417 column 2), anticipating claims 6-9 of the instant application.
Phillips teaches that 2 mL liposomes with 60 mM total lipid were labeled with rhenium-186 BMEDA containing 115 mCi (page 418 column 1). By the Examiner’s calculations, 2 mL of liposomes with 60 mM total lipid (DSPC: cholesterol 55:45 molar ratio) is approximately 81 mg of lipid. 115 mCi per 81 mg of lipid is approximately equal to 71 mCi per 50 mg of lipid, which is within the range of 0.01 mCi to 400 mCi per 50 mg of lipid as recited in claim 10 of the instant application.
Phillips’ teaching of a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1) anticipates claims 12-14 of the instant application.
Phillips teaches that the liposomes were administered by convection-enhanced delivery (page 418 column 2) with infusion of volumes of 50 µL and 100 µL into subjects at a rate of 2 µL/min (page 420 column 1). Administration via infusion anticipates claim 16 of the instant application. Administration via convection-enhanced delivery (which is a process based on infusion) anticipates claim 17 of the instant application. Infusion at a rate of 2 µL/min anticipates claim 19 of the instant application. Infusion of 100 µL, which is equal to 0.1 mL, anticipates claim 21 of the instant application.
Phillips’ teaching that 25 µL of a 2 mL liposome solution containing 115 mCi (page 418 column 1, page 420 column 2), therefore, approximately 1.4 mCi is present in the 25 µL fraction anticipates instant claim 20. According to MPEP 2131.03(i), a specific example in the prior art which is within the claimed range anticipates the range, therefore, Phillips’ teaching of 1.4 mCi anticipates the instantly claimed range of 1 to 50 mCi as recited in instant claim 20.
Phillips teaches that during convection-enhanced delivery of radiolabeled liposomes the subjects were imaged by SPECT/CT (page 418 column 2, figures 1 and 2). Further SPECT imaging was done subsequent to radiolabeled liposome administration (page 418 column 2). Phillips’ teaching of imaging radiolabeled liposomes during convection-enhanced delivery anticipates claim 23 of the instant application. Phillips’ teaching of imaging radiolabeled liposomes after administration anticipates claim 24 of the instant application.
However, in the event that the previous does not have sufficient specificity to rise to anticipation, claims 1, 2, 4-10, 12-14, 16, 17, 19 - 21, 23, and 24 are also rejected under 35 U.S.C. 103 below.
Claim Rejections - 35 USC § 103 (Maintained)
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 non-obviousness.
Claims 1, 2, 4-10, 12-14, 16, 17, and 19 - 24 are rejected under 35 U.S.C. 103 as being unpatentable over Phillips (as cited above, of record).
For the purposes of this ground of rejection only, and purely arguendo, the examiner will take the position that Phillips does not teach a specific embodiment (i.e., preferred embodiment, working example, etc.) having all of the claimed elements arranged as required by the claim without resorting to some “picking and choosing” within the prior art disclosure. That being said, although Phillips thus would not be anticipatory by this interpretation of the facts, it nevertheless does fairly suggest the claimed invention, as shown below.
As discussed above, Phillips teaches a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1). Phillip’s liposomes were radiolabeled with rhenium-186 BMEDA (N,N-bis(2-mercaptoethyl)-N’,N’-diethylenediamine) (page 418 column 1).
Phillips’ method for administering 186Re-labeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1) reads on claim 1 of the instant application which recites a method of treating a central nervous system disease by administering a therapeutically effective radiolabeled liposome.
Phillips teaches that 2 mL liposomes with 60 mM total lipid were labeled with rhenium-186 BMEDA containing 115 mCi (page 418 column 1), then 25 µL were injected (page 420 column 2). With consideration of the injection volume (25 µL) being 1/80th of the initial liposome formulation volume (2 mL), approximately 1.4 mCi is present in the 25 µL fraction. Phillips’ teaching of 1.4 mCi overlaps on the instantly claimed range of 1 to 250 mCi as recited in instant claim 1. Claimed ranges that overlap with teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
Notably, the instant specification states that the term “delivered” is interchangeable with the term “administered” (paragraph 0059), therefore the administration of 1.4 mCi in 25 µL reads on the limitation of “delivered to” in claim 1.
Phillips’ use of rhenium-186 BMEDA reads on claims 2 and 4 of the instant application, which recite R groups for the radiolabeled compound that are consistent with BMEDA (claim 2) and that the metal is rhenium-186 (claim 4).
Phillips teaches that rhenium-186 BMEDA was loaded into liposomes via an ammonium pH gradient (page 418 column 1), reading on claim 5 of the instant application which recites the compound is incorporated into the liposome.
Phillips’ liposomes were composed of distearoylphosphatidylcholine and cholesterol (page 417 column 2), reading on claims 6-9 of the instant application which recite that the liposomes are comprised of a lipid (claim 6), a phospholipid (claim 7), a cholesterol or cholesterol analogue (claim 8), and distearoyl phosphatidylcholine (claim 9).
Phillips teaches that 2 mL liposomes with 60 mM total lipid were labeled with rhenium-186 BMEDA containing 115 mCi (page 418 column 2). By the Examiner’s calculations, 2 mL of liposomes with 60 mM total lipid (DSPC: cholesterol 55:45 molar ratio) is approximately 81 mg of lipid. 115 mCi per 81 mg of lipid is approximately equal to 71 mCi per 50 mg of lipid, which is within the range of 0.01 mCi to 400 mCi per 50 mg of lipid as recited in claim 10 of the instant application. Claimed ranges that overlap with those taught by the prior art are prima facie obvious according to MPEP 2144.05(i).
Phillips’ teaching of a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1) reads on claims 12-14 of the instant application which recite that the disease is a cancer (claim 12) and that the cancer is a glioblastoma (claims 13 and 14).
Phillips teaches that the liposomes were administered by convection-enhanced delivery (page 418 column 2) with infusion of volumes of 50 µL and 100 µL into subjects at a rate of 2 µL/min (page 420 column 1). Administration via infusion reads on claim 16 of the instant application. Administration via convection-enhanced delivery reads on claim 17 of the instant application. Infusion at a rate of 2 µL/min reads on claim 19 of the instant application. Infusion of 100 µL, which is equal to 0.1 mL, overlaps on the claimed range of 0.1 mL to 25 mL, as recited in claim 21 of the instant application.
Phillips’ teaching of 1.4 mCi radioactivity injected in a liposome solution(page 418 column 1, page 420 column 2) overlaps on the instantly claimed range of 1 to 50 mCi as recited in instant claim 20. Claimed ranges that overlap with teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
With similar calculations as above, Phillips’ teaching for 2 mL liposome solution containing 115 mCi (page 418 column 1) is approximately 57.5 mCi/mL. Although 57.5 mCi/mL does not overlap the instantly claimed range of about 0.1 to about 50 mCi/mL it is very close, and absent a showing of criticality the difference between the claimed range and Phillips’ teaching is negligible, therefore 57.5 mCi/mL is prima facie obvious according to MPEP 2144.05(i).
Phillips teaches that during convection-enhanced delivery of radiolabeled liposomes the subjects were imaged by SPECT/CT (page 418 column 2, figures 1 and 2). Further SPECT imaging was done subsequent to radiolabeled liposome administration (page 418 column 2). Phillips’ teaching of imaging radiolabeled liposomes during convection-enhanced delivery reads on claim 23 of the instant application. Phillips’ teaching of imaging radiolabeled liposomes after administration reads on claim 24 of the instant application.
Claims 1, 2, 4-10, 12-14, 16, 17, and 19 - 24 are rendered prima facie obvious over the teachings of Phillips, because it is prima facie obvious to combine prior art elements according to known methods, in order to yield predictable results. In the instant case, all the claimed elements (e.g., radiolabeled BMEDA, 186-Re, liposomes) were known in the prior art (e.g., brachytherapy) and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results (e.g., a method for treating cancer with radiolabeled liposomes) to one of ordinary skill in the art (MPEP 2143(i)(a)).
Claims 3 is rejected under 35 U.S.C. 103 as being unpatentable over Phillips (as cited above, of record) and further in view of Bao ("A novel liposome radiolabeling method using 99mTC-"SNS/S" complexes: in vitro and in vivo evaluation" Journal of Pharmaceutical Sciences 2003, of record).
As discussed above, Phillips teaches a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1). Phillip’s liposomes were radiolabeled with rhenium-186 BMEDA (N,N-bis(2-mercaptoethyl)-N’,N’-diethylenediamine) (page 418 column 1).
Phillips does not teach the radiolabeled compound has R groups of R1 is CH2CH2CH2CH3 and R2 is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3) (claim 3) or that the amount of radioactivity delivered by the radiolabeled liposome is from about 0.1 mCi to about 50 mCi (claim 20).
Bao teaches the missing elements of Phillips.
Bao teaches liposomes radiolabeled with 99mTc BMBuA (N,N-bis(2-mercaptoethyl)-1-butylamine) (page 1894), suggesting that different compounds may result in different labeling efficiencies (abstract). Bao’s experiments showed that BMBuA labeling had increased efficiency over the other compounds evaluated (Table 1).
The combination of Phillip’s teachings of a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1) with Bao’s teachings of radiolabeling liposomes with 99mTc BMBuA reads on claim 3 of the instant application.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of Phillips and Bao for a method of administering radiolabeled liposomes to treat cancer. A person of ordinary skill in the art would have been motivated to modify the method of Phillips with BMBuA as taught by Bao because Bao teaches that BMBuA has increased labeling efficiency over other compounds. The combination of Phillips and Bao is prima facie obvious as combining prior art elements according to known techniques to yield predictable results (MPEP 2143(i)(a)).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Phillips (as cited above, of record) in view of Li (as cited above, of record).
As discussed above, Phillips teaches a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1).
Phillips does not teach the treatment molecules attached to the liposomes (claim 11).
Li teaches the missing element of Phillips.
As discussed above, Li teaches a method for administering radiolabeled liposomes to a subject for the treatment of breast cancer (page 2515 column 2). Li teaches that panitumumab and bevacizumab, two monoclonal antibodies, are conjugated to the radiolabeled liposomes (page 2514 column 2).
The combination of Phillips’ teaching for a method of administering radiolabeled liposomes to a subject (page 420 column 1) with Li’s teaching of monoclonal antibodies attached to the liposome (page 2514 column 2) reads on claim 11 of the instant application because monoclonal antibodies are treatment molecules.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of Phillips and Li for a method of administering radiolabeled liposomes to with attached treatment molecules. A person of ordinary skill in the art would have been motivated to apply the method of Phillips for administering radiolabeled liposomes to subjects (page 420 column 1) with Li’s teaching of attached treatment molecules (page 2514 column 2) in order to add therapeutic benefit to the liposomes. The combination of Phillips and Li is prima facie obvious as combining prior art elements according to known techniques to yield predictable results (MPEP 2143(i)(a)).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Phillips (as cited above, of record) and further in view of Chamberlain (“Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials” Neuro-Oncology 2014, of record).
As discussed above, Phillips teaches a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1).
Phillips does not teach the treatment of leptomeningeal metastases (claim 15).
Chamberlain teaches the missing element of Phillips.
Chamberlain shows several studies that have examined liposomal delivery of chemotherapeutic drugs as compared to the administration of free drug for the treatment of leptomeningeal metastases (Table 1). Chamberlain teaches that liposomal therapies had superior efficacy in the treatment of leptomeningeal metastases compared to non-liposomal treatments (abstract).
The combination of Phillips’ teaching for a method of administering radiolabeled liposomes to a subject (page 420 column 1) with Chamberlain’s teaching that liposomal therapies have superior efficacy in the treatment of leptomeningeal metastases (abstract) reads on claim 15 of the instant application, which recites the administration of radiolabeled liposomes is for the treatment of leptomeningeal metastases.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of Phillips and Chamberlain for a method of administering radiolabeled liposomes to treat leptomeningeal metastases. A person of ordinary skill in the art would have been motivated to apply the method of Phillips for administering radiolabeled liposomes to subjects (page 420 column 1) with leptomeningeal metastases because Chamberlain teaches that liposomal therapies have superior efficacy in the treatment of leptomeningeal metastases compared to non-liposomal therapies (abstract). The combination of Phillips and Chamberlain is prima facie obvious as combining prior art elements according to known techniques to yield predictable results (MPEP 2143(i)(a)).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Phillips (as cited above, of record) and further in view of Mehta (“Convection-Enhanced Delivery” Neurotherapeutics 2017, of record).
As discussed above, Phillips teaches a method for administering radiolabeled liposomes to a subject for the treatment of glioblastoma (page 420 column 1). Phillips teaches that the radiolabeled liposomes were administered by convection-enhanced delivery (page 418 column 2).
Phillips does not teach that the convection-enhanced delivery comprises the administration of the radiolabeled liposomes via one or more catheters (claim 18).
Mehta teaches the missing element of Phillips.
Mehta teaches that convection-enhanced delivery is a technique for delivering therapeutics to malignant gliomas, among other neuro-centric diseases (abstract). Mehta teaches that convection-enhanced delivery allows for the bypassing of the blood-brain barrier (which traditionally hampers drug delivery for neurological diseases), allows for targeted delivery, and the perfusion of target sites (page 358 column 2 to page 359 column 1). Mehta teaches that one or more catheters are used to deliver compounds for convection-enhanced delivery (page 359 column 1).
The combination of Phillips’ teachings to administer radiolabeled liposomes via convection-enhanced delivery (page 418 column 2) with Mehta’s teaching that one or more catheters are used in convection-enhanced delivery (page 359 column 1) reads on claim 18 of the instant application.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of Phillips and Mehta for a method of administering radiolabeled liposomes by convection-enhanced delivery via one or more catheters. A person of ordinary skill in the art would have been motivated to apply the teachings of Mehta, that one or more catheters are used in convection-enhanced delivery (page 359 column 1) to the method of Phillips for administering radiolabeled liposomes via convection-enhanced delivery (page 418 column 2) because Mehta teaches that convection-enhanced delivery uses one or more catheters. The combination of Phillips and Mehta is prima facie obvious as combining prior art elements according to known techniques to yield predictable results (MPEP 2143(i)(a)).
Examiner’s Reply to Attorney Arguments Dated September 22, 2025
Applicant argues that the prior art of Phillips’ does not teach the amended claim limitation of “wherein the amount of radioactivity delivered to the central nervous system by the radiolabeled liposome is from about 1 mCi to about 250 mCi” (Remarks pages 8 and 10). The Examiner disagrees, because as noted in the body of the rejection above, Phillips teaches that 2 mL liposomes with 60 mM total lipid were labeled with rhenium-186 BMEDA containing 115 mCi (page 418 column 1), then 25 µL were injected (page 420 column 2). With consideration of the injection volume (25 µL) being 1/80th of the initial liposome formulation volume (2 mL), approximately 1.4 mCi is present in the 25 µL fraction. Phillips’ teaching of 1.4 mCi overlaps on the instantly claimed range of 1 to 250 mCi as recited in instant claim 1. Notably, the instant specification states that the term “delivered” is interchangeable with the term “administered” (paragraph 0059), therefore the administration of 1.4 mCi in 25 µL reads on the limitation of “delivered to” in claim 1.
Since the terms “delivered” and “administered” are interchangeable according to the instant specification (paragraph 0059), Phillips’ teaching is anticipatory according to MPEP 2131.03(i), which discloses that a specific example in the prior art which is within the claimed range anticipates the range.
In arguendo, the Examiner will take the position that Phillips does not teach a specific embodiment (i.e., preferred embodiment, working example, etc.) having all of the claimed elements arranged as required by the claim without resorting to some “picking and choosing” within the prior art disclosure. Phillip’s teaching that 2 mL liposomes with 60 mM total lipid were labeled with rhenium-186 BMEDA containing 115 mCi (page 418 column 1), then 25 µL were injected (page 420 column 2) - which is approximately 1.4 mCi is present in the 25 µL fraction – overlaps on the instantly claimed range of 1 to 250 mCi as recited in amended claim 1. Claimed ranges that overlap with teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
Applicant argues that dependent claims are allowable by virtue of their dependence on allegedly allowable claim 1 (Remarks pages 10 – 13), however, as discussed above instant claim 1 is anticipated or, in arguendo, obvious over Phillips. As such, the 35 U.S.C. 102 and 35 U.S.C. 103 rejections over Phillips, and 35 U.S.C. rejections over Phillips in view of Bao, Li, Chamberlain, and Mehta, respectively are maintained.
Conclusion
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Toriana N. Vigil whose telephone number is (571)270-7549. The examiner can normally be reached Monday - Friday 9:00 a.m. - 5:00 p.m. EST.
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/TORIANA N. VIGIL/Examiner, Art Unit 1612
/FREDERICK F KRASS/Supervisory Patent Examiner, Art Unit 1612