-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 .
Applicant’s response dated May 4, 2026 is acknowledged.
Priority
This application is a 371 of PCT/US2023/061583 filed on 01/30/2023, and claims benefit in provisional application 63/304,403 filed on 01/28/2022.
Claim Status
Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, 39, 41-45, and 48 are pending. Claims 2, 3, 7-11, 13-20, 25-28, 31, 33-35, 37, 38, 40, 46, 47, 49, and 50 cancelled. Claims 1, 4, 43, and 44 were amended. Claims 41-45 and 48 are withdrawn. Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, and 39 are examined on the merits.
Election/Restriction
Applicant’s election with traverse of Group I (Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, 39, 41, and 42), drawn to a method in the reply filed on May 4, 2026, is acknowledged.
Applicant’s election of 7-DHC as the species of the claimed compound is acknowledged. Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, and 39 read on the elected species.
The traversal is on the ground that the claims were amended to require that the one or more doses of the radiation therapy are administered in an effective amount to induce the 7- dehydrocholesterol (7-DHC) or analog or derivative thereof to form a radical species that initiates and propagates radical chain reactions enhancing the efficacy of the one or more doses of the radiation therapy, which is not taught by Kamijo. Nothing in the reference suggests that a substrate compound described by the claims could or would lead to the improved efficacy of a radiation therapy.
Applicant’s arguments were fully considered, however they are unpersuasive because the common technical feature among the inventions is a compound of formulae I-VI, which was shown to be known in the prior art. Added wherein clauses that describe compound properties are not sufficient to distinguish the common technical feature from the prior art because compound properties, including those instantly claimed, would have been present in the prior art compound because a compound and its properties are inseparable.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claims 43-45 and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being withdrawn to a non-elected invention, and non-elected species of the invention, there being no allowable generic or linking claims. Please note that after a final requirement for restriction, the Applicants, in addition to making any response due on the remainder of the action, may petition the Commissioner to review the requirement. Petition may be deferred until after final action on or allowance of claims to the invention elected, but must be filed not later than appeal. A petition will not be considered if reconsideration of the requirement was not requested. (See § 1.181.).
Response to the restriction requirement of March 4, 2026 was timely filed.
Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, and 39 are examined on the merits.
Claim Objections
Claim 21 is objected to because “the nanoparticle have” is not grammatical. Objection may be obviated by replacing nanoparticle with nanoparticles.
Claims 23 and 24 are objected to for reciting the acronym NTSR1. The full name is required to appear at least once in the claims and the acronym may be used thereafter.
Claim 39 is objected to because it starts with “Th”.
Claim Rejections – 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, and 39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a tumor from CT26 cells by injecting 7-DHC in PLGA nanoparticles followed by IR radiation (320 kV, 3 Gy) and treating a tumor from H2199 cells by injecting 7-DHC liposomes followed by applying radiation therapy (5 Gy) to tumor post particle injection, does not reasonably provide enablement for treating any disease or disorder by administering 7-DHC, analog, or derivative thereof and one or more doses of radiation therapy; treating cancer; treating radiosensitive cancer; treating radioresistant cancer; treating vascular cancer, bone cancer, muscle cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colo-rectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, uterine cancer, and germ cell cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The applicants' attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention: Claim 1 encompasses methods of treating a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising an effective amount of 7-DHC or analog or derivative thereof, and one or more doses of radiation therapy. Claim 4 limits radiation therapy to X-rays, gamma rays, protons, neutrons, photodynamic therapy, or ionizing radiation therapy. Claims 5, 6, and 12 limit the 7-DHC or analog or derivative thereof to those encapsulated or incorporated into nanoparticles including polymeric nanoparticles, lipoprotein-like nanoparticles, liposomes, inorganic, and lipoprotein. Claim 29 limits the patient population to cancer patients. Claim 30 limits the patient population to cancer patients having radiosensitive cancer and radioresistant cancer. Claim 32 limits the patient population to cancer patients with vascular cancer, bone cancer, muscle cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colo-rectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, uterine cancer, and germ cell cancer.
(2) the state of the prior art: methods of treating diseases and methods of treating cancer are known in the art.
(3) the relative skill of those in the art is high and includes oncology specialists.
(4) the predictability or unpredictability of the art: treating diseases is unpredictable and treating cancer is unpredictable.
(5) the breadth of the claims: the claims are broad and encompass treating any disease with any radiation therapy and any composition that contains 7-DHC or analog or derivative thereof.
(6) the amount of direction or guidance presented: the specification does not provide any guidance that provides a biochemical basis for expecting successfully treating a subject having any disease or disorder by administering 7-DHC or analog or derivative and one or more doses of radiation therapy to the subject.
(7) the presence or absence of working examples: the specification provides two working examples of treating mice having a tumor of CT26 cells and treating mice having a tumor of H2199 cells where each mice population was administered a specific nanoparticle composition containing 7-DHC followed by specific radiation therapy.
(8) the quantity of experimentation necessary: a person skilled in the art would have to determine diseases that can be treated with the claimed combination of therapies and subsequently determine which type of pharmaceutical composition would be required to deliver the 7-DHC or analogs or derivative thereof. The claims do not limit route of administration and the skilled artisan would have to find which routes are suitable for delivering said compounds. The skilled artisan would also have the task of determining which analogs and derivatives of 7-DHC or 7-DHC itself would work for treating the diseases. Similarly, the skilled artisan would have to determine the type of radiation therapy that would work in treating the diseases. The same analysis applies to treating cancers as described in claims 29, 30, and 32. The results obtained for treating the two cancer cells lines are not sufficient to show that there is enablement for treating every cancer.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-6, 12, 21-24, 29, 30, 32, 36, and 39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 requires an analog of 1-dehydrocholesterol (7-DHC). The claim is indefinite because the specification does not define what constitutes an analog of 7-DHC and therefore the scope of the term is unknown.
Claims 6 and 12 recite “lipoprotein-like”. The claims are indefinite because the addition of the word "like" to an otherwise definite expression (e.g. lipoprotein) extends the scope of the expression so as to render it indefinite.
Claim 21 recites the limitation "the nanoparticle" in line 1. There is insufficient antecedent basis for this limitation in the claim. Ground of rejection may be obviated by replacing nanoparticle with nanoparticles, which is supported in claim 5.
Claims 4, 5, 22-24, 29, 30, 32, 36, and 39 are indefinite because the claims depend from an indefinite base claim.
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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1, 4-6, 12, 21, 29, 30, 32, 36, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Chemical Communication, 2019, 55, 14081-14084) and Singh (WO 2015/157262 A1 Published October 15, 2015).
The claims encompass a method of treating a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising an effective amount of 7-DHC, and one or more doses of radiation therapy; wherein the one or more doses of radiation therapy are administered in an effective amount to induce the 7-DHC to form a radical species that initiates and propagates radical chain reaction enhancing the efficacy of the one or more doses of the radiation therapy; optionally wherein the subject has cancer.
The teachings of Wang are related to incorporation of 7-DHC into liposomes to enhance the anticancer activity of photosensitizer-encapsulated liposomes upon irradiation. The photooxidation of 7-DHC into its endoperoxide form by singlet oxygen may account for the enhanced therapeutic effect, realizing an efficient combination of photodynamic therapy and photoactivated chemotherapy (Abstract). Photodynamic therapy (PDT) has attracted much attention in recent years as a non-invasive, selective and safe method for treatment of cancer, and works by light excitation of nontoxic photosensitizers (PSs), followed by energy or electron transfer with oxygen to generate cytotoxic reactive oxygen species (ROS). Liposomal delivery of PSs is a useful way to solve this problem. Liposomes are vesicles composed of phospholipids (e.g. phosphatidylcholine (PC)), and cholesterol (CHOL) is often included as an indispensable component to improve the rigidity of the bilayer membrane structure. By virtue of their perfect biocompatibility, liposomes have found wide applications in drug delivery. The encapsulation of PSs in liposomes may not only enable them to be delivered by common administration routes, but also inhibit aggregation induced quenching to maintain efficient singlet oxygen generation (left column on page 14081). To achieve better efficacy against cancer, two or more drugs or therapies are usually combined to capitalize on the additive or synergetic effect. The combination of PDT with chemotherapy has witnessed promising treatment results, and liposomes are ideal delivery platforms for dual PDT and chemotherapy due to their ability to encapsulate both hydrophobic and hydrophilic cargos (right column on page 14081). Light excitation of 7-DHC and PS-based liposomes may generate singlet oxygen, part of which then oxidize 7-DHC into CEP (7-dehydrocholesterol endoperoxide), realizing PDT and photoactivated chemotherapy simultaneous. See Scheme 1. (paragraph bridging columns on pages 14081-14082). Cytotoxicity of liposomes A-D toward human ovary cancer (SKOV-3 cells, purchased from Beijing Cancer Hospital) was evaluated using MIT assay (Fig. 3). A and B are almost nontoxic no matter in the dark or under light irradiation, in line with their good biocompatibility. Liposome C based on CHOL and TPP displayed phototoxicity with an IC50 value of 236.9 μg ml-1, corresponding to a TPP concentration of 0.156 μM. Incorporation of 7-DHC instead of CHOL increased the phototoxicity of liposome D efficiently, with an IC50 value (128.5 μg m1-1 for liposome and 0.087 μM for TPP) about half of that of liposome C (Table Sl and Fig. S4, S5, ESI). MIT assay of C and D towards human lung cancer cells (A549, obtained from Peking Union Medical College Hospital) gave similar results (Fig. S5, ESI). In situ formation of CEP may mainly account for its enhanced cytotoxicity. Besides the additive/synergetic effect between singlet oxygen and CEP, the transformation from 7-DHC to CEP may increase the bioavailability
of singlet oxygen. Due to its short lifetime and therefore small range of action (< 20 nm), some singlet oxygen generated in liposomes may decay to the ground state before reacting with
biomolecules. In the presence of plenty of 7-DHC in liposomes, such a case may largely be inhibited by reacting with 7-DHC. Though still being a conjecture, incorporation of 7-DHC indeed provide a simple, universal and efficient way to enhance therapeutic effect of PSs encapsulated in liposomes. Apoptosis is a common cell death pathway induced by PDT. It
is often accompanied by changes in cell morphology which can be investigated by bright field microscopy. As shown in Fig. S6 (ESI), upon irradiation (420 nm laser) for different times, the SKOV-3 cells incubated with liposome D (100 μg ml-1) shrank accompanied by appearance of many vacuoles, which is one typical character of apoptotic cells.16 Then Annexin V-propidium iodide (PI) assay was carried out (Fig. S7, ESI). Annexin V can detect phosphatidylserine externalization, a hallmark of the early phase of apoptosis, and PI can stain the nuclei of necrotic cells. As shown in Fig. S7 (ESI), neither the fluorescence of Annexin V nor that of PI was observed for SKOV-3 cells incubated with liposomes A and B (100 μg ml-1) no matter in the dark or under light irradiation, which is consistent with their low toxicity. Only faint green fluorescence was observed for liposome C under irradiation, while much more distinct signal appeared for liposome D under the same condition (Fig. 4a). These results indicate that liposomes C and D cause cell death mainly through apoptosis, and incorporation of 7-DHC can efficiently enhance the therapeutic effect of liposome D, consistent with the MIT results. (left column on page 14083).
Wang does not teach administering the liposomes and photodynamic therapy to a subject in need thereof.
The teachings of Singh are related to compositions comprising 7-DHC derivatives in methods of treating cancer in a subject (Abstract). Cancer includes ovarian cancer (page 8 lines 14-22). Cancer treatment includes surgery, radiation and/or chemotherapy, based upon the type, location and dissemination of cancer. Surgery and localized radiation therapy may present lower toxicities to healthy cells and tissues, while chemotherapy is the best treatment option for disseminated cancer, leukemia, lymphoma, and metastasized cancers. Not all tumors respond to chemotherapeutic agents. Other tumors, although initially responsive to chemotherapeutic agents, may develop resistance, with cancer eventually recuring (bottom of page 1). The compositions include liposomal preparations (page 48 lines 11-24).
The teachings of Wang and Singh are related to compositions intended for treating ovarian cancer and it would have been obvious to have combined their teachings because they are in the same field of endeavor.
Regarding claim 1, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have treated ovarian cancer in a subject need thereof comprising administering a liposome composition comprising 7-DHC and photodynamic therapy to the subject, with a reasonable expectation of success because Wang teaches that exposing ovarian cancer cells SKOV-3 to liposomes made from PC, 7-DHC, and TPP and photodynamic therapy causes cells death through cell apoptosis. While Wang does not explicitly teach administering the composition and photodynamic therapy to a subject in need thereof, treating ovarian cancer by administering to a subject in need thereof a liposomal composition comprising an active agent including derivatives of 7-DHC was known from Singh. One of skill in the art would have been capable of determining a therapeutically effective amount of 7-DHC through routine experimentation. The “wherein” clause describes the effects of the method steps and it would have been reasonable to expect the effects to be present in the prior art method because the prior art method teaches the same method steps as claimed. See MPEP 2111.04.
Regarding claim 4, Wang teaches photodynamic therapy.
Regarding claims 5, 6, 12, and 21, Wang teaches liposomes having a particle size in the nanometer range (See Figure 1). The particle size range in claim 21 is obvious because it overlaps with the range shown in Figure 1. Nanosized liposomes read on nanoparticles. Since the scope of “lipoprotein-like” is unknown because the term is indefinite, nanosized liposomes described by Wang render the limitation obvious.
Regarding claim 29, prior art method is a method of treating a patient with ovarian cancer. The composition in Wang’s method is the same as claimed and it would have enhanced the treatment of cancer compared to administration of the one or more doses of radiation therapy alone, absent evidence to the contrary.
Regarding claim 30, SKOV 3 cell line is radioresistant and it would have been obvious to have treated ovarian cancer that is radioresistant.
Regarding claim 32, Wang teaches ovarian cancer.
Regarding claim 36, it would have been obvious to have administered the liposome composition followed by photodynamic therapy because Wang teaches that CEP was generated in situ upon irradiation of liposome D (paragraph bridging columns on page 14082). This teaching implies that the liposomes were contacted with the cells first followed by irradiation to generate CEP.
Regarding claim 39, Wang teaches 7-DHC.
Claims 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wang and Singh as applied to claims 1, 4-6, 12, 21, 29, 30, 32, 36, and 39 above, and further in view of Ellens (WO 02/36073 A2 Published May 10, 2002) and Norris (Journal of Pathology, 2019, 248, 352-362).
The claims further define the method of claim 5 by requiring the nanoparticles to comprise a targeting agent coupled thereto.
The teachings of Wang are relied upon as summarized above, however Wang does not teach the limitations of claims 22-24.
The teachings of Ellens are related to liposomes comprising a targeting ligand which comprises a non-biological, biometric antagonist to a receptor that is upregulated at a disease site (Abstract). Approaches have been taken to provide site-specific delivery of liposomes. In such approaches, a targeting ligand may be attached to the liposome surface, typically by coupling to a lipid comprising the liposomal bilayer. Targeting ligands have typically included antibodies, antibody fragments, peptides and other biological materials such as certain vitamins and sugars, especially antibodies and antibody fragments (page 1 lines 20-25). The liposomes preferably comprise a therapeutic or diagnostic active agent, more preferably selected from anti-neoplastic agents, anti-inflammatory agents, anti-infective agents, diagnostic imaging agents and combinations thereof (page 4 lines 21-23). Liposomes are useful in treating ovarian cancer (paragraph bridging pages 22-23).
Ellens does not teach receptors that are upregulated on ovarian cancer cells.
The teachings of Norris are related to determining the role of neurotensin (NTS) in high grade serous ovarian carcinoma (HGSC), five ovarian cancer (OvCa) cell lines were screened for expression of NTS and its receptors, NTSR1 and NTSR3. Increased expression of NTS and NSTR1 was observed in several of the OvCa cells, whereas the NTSR3 receptor was lower in all OvCa cells, compared to immortalized FT epithelial cells. Treatment with NTSR1 inhibitor (SR48692) decreased cell proliferation, but increased cell migration in OvCa cells. The effects of SR48692 were receptor mediated, since transient RNAi knockdown of NTSR1 mimicked the migratory effects and knockdown of NTSR3 mimicked the anti-proliferative effects (Abstract).
NTS, encodes for the 13-arnino acid neuropeptide, NTS, which acts as an autocrine/paracrine signaling molecule in the nervous and gastrointestinal system. Dysregulation of NTS or one of its three receptors (NTSRl, NTSR2, NTSR3) has been reported in a variety of cancers. In EOC, increased expression of NTS and its high affinity receptor NTSRl compared to normal ovarian epithelium has been reported and overexpression of NTSRl was associated with platinum resistance and poor prognosis (bottom of right column on page 358). When co-expressed, NTSRl and NTSR3 interact to augment the cellular response to NTS, in part by formation of a heterodimer that is internalized following ligand stimulation. Thus, SR48692 can inhibit the NTSRl receptor directly or the NTSR3 receptor indirectly by preventing internalization and signal transduction. Recently, SR48692 has been proposed as a potential therapy in EOC based on increased expression of NTSRl. The present study suggests that the potential therapeutic effects of SR48692 may occur via either receptor. For example, the growth
inhibitory effects of SR48692 were mimicked by NTSR3 knockdown in our study which is consistent with prior studies (bottom left column on page 359).
The teachings of Wang, Ellens, and Norris are related to ovarian cancer and it would have been obvious to have combined them because they are in the same field of endeavor. It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified Wang’s liposomes by coupling thereto a targeting ligand that is an antagonist of a receptor that is upregulated in ovarian cancer cells in order to improve delivery of the liposome to the targeted site, with a reasonable expectation of success because Ellens teaches that therapeutic liposomes intended for treating ovarian cancer may be coupled to an antagonist of a receptor that is upregulated at a disease site in order to improve delivery of the liposome to the target disease site. It would have been obvious to have SR48692 as the targeting ligand because it was known from Norris that NTSR1 is upregulated in ovarian cancer cells and that SR48692 is an antagonist of NTSR1. The selection of a known material based on its suitability for its intended purpose supports obviousness and combining prior art elements according to known methods to obtain predictable results supports obviousness.
Conclusion
No claims are allowed.
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/ALMA PIPIC/Primary Examiner, Art Unit 1617
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