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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10, in the reply filed on 03/27/2026 is acknowledged.
Accordingly, claims 24-28 and 36-40 are withdrawn as being directed to a non-elected invention. Claims 4, 6-7, 10, 27-28, and 38-40 are amended and claims 11-23, 29-35, and 41-46 are canceled. Claims 1-10 are examined on the merits herein.
Priority
The instant application filed 03/13/2024, is a 371 filing of PCT/US22/76676, filed 09/19/2022, which claims benefit to U.S. Provisional Application No. 63/261,320, filed 09/17/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/22/2024 and 03/13/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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 1-10 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 contains the trademark/trade name “lipiodol”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe ethiodized oil and, accordingly, the identification/description is indefinite.
The term “effective amount” in claim 1 is a relative term which renders the claim indefinite. The term “effective amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The instant specification simply defines “effective amount” as the quantity of active therapeutic agent sufficient to yield a desired therapeutic response without adverse side effects ([0058]). Such a definition fails to provide a distinct standard for how much to administer nor what specifically constitutes an “effective amount”. For the sake of compact prosecution, any amount not demonstrating extreme toxicity will be considered an “effective amount”.
Claim 7 recites the limitation "the immunotherapeutic", however, parent claim 1 does not recite any such element. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 10, the phrase "preferably" and the use of parentheses renders the claim indefinite because it is unclear whether the limitations following “preferably” and within the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Claim 10 further recites percent concentration without reciting the basis for such percents. For example, are the amounts based on the total volume of the composition, the total volume of the aqueous phase, or something else? For the sake of compact prosecution, the claim will be interpreted as a concentration based on the volume of the total composition.
The remaining claims are rejected by virtue of their dependency on claim 1.
Claim Rejections - 35 USC § 102
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.
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, 4-5, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kodama T, et al. (1988). [Pharmacological and clinical studies on lipiodol emulsion for hepatocellular carcinoma]. Gan To Kagaku Ryoho. 15(8 Pt 2):2544-8 (PTO-892; google image translation used), hereinafter Kodama, as evidenced by GoodRx (2025). Doxorubicin. Reviewed by Baxley, A. and Ng, C. (PTO-829), hereinafter GoodRx.
Kodama teaches enhancing the antitumor effect of selective chemotherapy for hepatocellular carcinoma by preparing a Lipiodol emulsion using the contrast agent Lipiodol and the surfactant poloxamer-188 to achieve sustained release of the anticancer drug Adriamycin (abstract).
Regarding claim 1: Kodama discloses clinical applications of the Lipiodol emulsions (Lp-Em) in a study wherein 6 subjects with unresectable hepatocellular carcinoma (HCC) are treated by injecting Lp-Em into the hepatic artery, followed by transcatheter arterial embolization (TAE) (p. 2545, “clinical considerations” and “clinical applications of Lp-Em”). Such an application reads on a method of locoregionally delivering a bioaffecting agent to a subject in need of treatment for cancer, as instantly claimed. The Lipiodol emulsion is prepared using a 10% solution of the nonionic surfactant poloxamer-188 (Px) (i.e., a copolymer surfactant). 40 mg of Adriamycin (ADM) (i.e., a bioaffecting agent) was dissolved in Px, mixed with Lipiodol, and then stirred to create an emulsion (p. 2544, “basic examination”; Table 1). Such a preparation method read fully on step i) of the instant invention. As already discussed, Lp-Em was injected into the hepatic artery in subjects with unresectable HCC, followed by TAE (p. 2545, “clinical considerations” and “clinical applications of Lp-Em”). Such a method reads on step ii) of the instant invention. Given that Lp-Em appeared to be an effective selective cancer chemotherapy for HCC (p. 2547, “summary”), it is concluded that the emulsion comprises an effective amount of the bioaffecting agent.
Regarding claim 2: The emulsion is delivered via injection into the hepatic artery followed by TAE (p. 2545, “clinical considerations” and “clinical applications of Lp-Em”), which reads on transarterial administration.
Regarding claims 4-5: The lipiodol emulsion comprises adriamycin, also known as doxorubicin, which is a chemotherapeutic drug as evidenced by GoodRx.
Regarding claim 10: The lipiodol emulsion is prepared by combining 5 ml of a 10% solution of poloxamer-188 with 10 ml of Lipiodol. Using the formula C1V1=C2V2, the examiner calculates that the emulsion comprises a final concentration of copolymer surfactant of 3.3% w/v. As best interpreted given the 112(b) issue identified above, an amount of 3.3% w/v falls within the instantly claimed range (i.e., 1-30%).
Claims 1-2 and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Higashi, S., et al. (1995), Arterial-injection chemotherapy for hepatocellular carcinoma using monodispersed poppy-seed oil microdroplets containing fine aqueous vesicles of epirubicin. Initial medical application of a membrane-emulsification technique. Cancer, 75: 1245-1254, (IDS dated 03/13/2024), hereinafter Higashi.
Higashi teaches the preparation of a long term inseparable, water-in-oil-in-water emulsion (W/O/W) for use in arterial-injection therapy for patients with HCC and its evaluation for clinical useful-ness (p. 1245, left col., first paragraph).
Regarding claim 1: W/O/W emulsions were prepared by dissolving epirubicin (i.e., a bioaffecting agent), in a glucose solution and mixing it with iodized poppy-seed oil (IPSO) (i.e., lipiodol, see Materials section). An aqueous phase containing normal saline and poloxamer-188 (i.e., a copolymer surfactant) was then added (p. 1246, right col., last paragraph). Such a preparation method reads on instantly claimed step i). The clinical application of W/O/W emulsions on Hepatocellular Carcinoma included a study of 21 patients diagnosed over approximately 1 year as having HCC (p. 1247, right col., final paragraph). Arterial infusions of W/O/W were administered through either of the proper hepatic artery, the right hepatic artery, the replacing right hepatic artery, etc. (p. 12448, left col., second paragraph). Such a method reads on step ii), while the patients read on subjects in need of treatment for cancer, as instantly claimed. The volume of W/O/W in one injection was approximately 17 ml. This injection contained 4-7 ml of IPSO and 8-60 mg of epirubicin (p. 1248, left col., third paragraph). The data shows that patients treated with a high dose (40 mg or greater) of epirubicin had a marked deposition of IPSO in the tumor tissue, with good clinical results regardless of whether gelatin-sponge particles were used (p. 1252, right col., final paragraph), thereby reading on an effective amount of the bioaffecting agent.
Regarding claim 2: The emulsions were delivered via arterial infusions (p. 12448, left col., second paragraph), which read on transarterial administration.
Regarding claim 4: In the case of cancer chemotherapy for HCC, anthracycline antibiotics such as doxorubicin and epirubicin are suitable (p. 1252, left col., final paragraph), evidencing the use of epirubicin as a chemotherapeutic drug.
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. Claims 1-5 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Kodama in view of Huang D, et al. (2017). TACE plus percutaneous chemotherapy-lipiodol treatment of unresectable pedunculated hepatocellular carcinoma. Medicine (Baltimore). 96(30):e7650 (PTO-892), hereinafter Huang.
The teachings of Kodama are discussed above, as are the rejections of claims 1-2, 4-5, and 10.
The teachings of Kodama differ from that of the instant invention in that Kodama does not explicitly disclose wherein the emulsion is delivered by intratumoral administration, as defined in claim 3.
Huang discloses the treatment and outcomes of unresectable Pedunculated hepatocellular carcinoma (P-HCC) treated with transcatheter arterial chemoembolization (TACE) and percutaneous chemotherapeutic agents lipiodol emulsion (CALE) injection. Patients underwent a median of 4 TACE sessions and received a median of 2 percutaneous CALE injections. TACE plus percutaneous CALE injection is a safe and effective treatment for unresectable P-HCC (abtract). Specifically, percutaneous intratumoral injection with CALE was adopted if angiography demonstrated that injection of CALE could not be administered completely via an arterial approach, and imaging modalities verified defects or poor deposition of CALE in the tumor after TACE (Discussion, para. 3). Results indicate that percutaneous CALE injection used for local ablation and supplementary therapy following TACE can improve survival of patients with unresectable P-HCC (p. 8, left col., para. 4). The emulsion comprises 30 to 50mg of epirubicin and 6 to 20mL of lipiodol (p. 2, right col., first paragraph). The percutaneous intratumoral injection reads on the intratumoral administration of claim 3.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to deliver the chemotherapy emulsion of Kodama via intratumoral administration, since such an administration method is known and routine in the art as taught by Huang. Huang teaches that intratumoral injection with a chemotherapeutic agent lipiodol emulsion (i.e., CALE) can be used following TACE methods to improve deposition of CALE in the tumor and improve survival of patients with unresectable HCC. Thus, one of ordinary skill in the art would have been motivated to administer the emulsion of Kodama via intratumoral injection, following TAE (TACE), to improve deposition and survival. Such a combination entails the use of a known technique to improve similar methods (i.e., TACE for treating unresectable HCC) in the same way. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification since Kodama and Huang teach methods of treating HCC with chemotherapeutic lipiodol emulsions and TAE/TACE.
2. Claims 1-2 and 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over Kodama in view of Ichim, T., (US 20070269406 A1, 11/22/2007, IDS dated 03/13/2024), hereinafter Ichim, as evidenced by Komal A, et al. (2021). TLR3 agonists: RGC100, ARNAX, and poly-IC: a comparative review. Immunol Res. 69(4):312-322 (PTO-892), hereinafter Komal.
The teachings of Kodama are discussed above, as are the rejections of claims 1-2, 4-5, and 10.
The teachings of Kodama differ from that of the instant invention in that Kodama does not explicitly disclose wherein the bioaffecting agent comprises an immunotherapeutic or immune boosting agent, as recited in claims 6 and 8, and further defined in claims 7 and 9.
Ichim discloses methods of inducing a cancer-specific immune response through administration of an immune stimulant in the context of tumor cell death induction (abstract). Specifically described is a method of modifying the transcatheter chemoembolization (TACE) procedure in order to induce an antitumor immune response in a patient with hepatic cancer. The method including the steps of: Administering a mixture of a single or plurality of immune stimulant(s) admixed with a clinically applicable localizing agent and/or with a single or plurality of agents capable of causing localized cell death and administering said combination directly into the tumor and/or arteries providing the tumor with blood supply using a catheter (claim 21). The patient may suffer from a localized primary hepatocellular carcinoma (claim 23). The mixture injected into the tumor feeding artery comprises a composition of an immune stimulant, lipiodol, and a chemotherapeutic agent at a concentration sufficient to induce localized tumor cell death, immune activation, and form a localized depot (claim 31). Said immune stimulant reads on the instantly claimed immune boosting/immunotherapeutic agent. The agent capable of increasing immune response may be an agonist of toll like receptors (claims 61 and 69; [0023]; [0029]), which reads on the instantly claimed TLR agonist. Chemotherapeutic agents include doxorubicin (claim 30; [0057]; [0059]). Specific examples disclose the injection of a composition comprising Poly (IC), lipiodol, and doxorubicin into the tumor feeding artery (claim 30; [0029]; [0057]). The emulsion is prepared with: 10 mL of Lipiodol, 50 mg doxorubicin and clinical grade Poly (IC) stabilized with carboxymethylcellulose ([0057]). Poly IC is a TLR3 agonist as evidenced by Komal.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to add an immune stimulant into the chemotherapy composition of Kodama, since immune stimulants are known and routine in the art as taught by Ichim. Ichim discloses the improvement of transcatheter chemoembolization procedures by injecting chemotherapy compositions comprising an immune stimulant in addition to the chemotherapeutic and localizing agent. As such, one of ordinary skill in the art could have applied the known technique of immune stimulation to improve the chemoembolization procedure of Kodama in the same way as taught by Ichim. Such an improvement is yielded by the addition of an immune stimulant into the chemotherapy composition. Additionally, both Kodama and Ichim teach delivering doxorubicin/lipiodol emulsions via arterial chemoembolization methods for the treatment of HCC. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose…[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). As such, the inventions of claims 6 and 8 are obvious.
It would have been further obvious to select a toll-like receptor (TLR) agonist as the immune stimulant since, TLR agonists are known and routine immune stimulants in the art as taught by Ichim. TLR agonists are known and effective immune stimulators which may be used in combination with chemotherapy agents such as doxorubicin to treat HCC tumors via chemoembolization. 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 such, the inventions of claims 7 and 9 are obvious.
One of ordinary skill in the art would have had a reasonable expectation of success in making the above modifications since Ichim teaches that immune stimulants, specifically TLR agonists, can be included in doxorubicin/lipiodol emulsions, similar to those of Kodama.
Conclusion
No claims allowed.
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/SUSANNAH S ARMSTRONG/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616
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