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 .
Status of Claims
Receipt of Remarks/Amendments filed on 07/16/2026 is acknowledged. Claims 1 and 7 are amended and claims 10-23, 29-35, and 41-46 are canceled. Claims 24-28 and 36-40 are withdrawn as being directed to a non-elected invention. Claims 1-9 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.
Withdrawn Objections/Rejections
Claims 1-10 were rejected under 35 U.S.C. 112(b) as being indefinite. Applicant’s amendments to the claims have overcome the rejections and the rejections are withdrawn.
Claims 1-2, 4-5, and 10 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kodama. Applicant’s amendments to the claims have overcome the rejection and the rejection is withdrawn.
Claims 1-2 and 4 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Higashi. Applicant’s amendments to the claims have overcome the rejection and the rejection is withdrawn.
The following grounds of rejection are necessitated by amendment:
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.
Claims 1-2 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over 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 (on record; google image translation used), hereinafter Kodama, as evidenced by GoodRx (2025). Doxorubicin. Reviewed by Baxley, A. and Ng, C. (on record), 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 (p. 8, 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. 9, “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 (i.e., ethiodized oil), and then stirred to create an emulsion (p. 8-9, “basic examination”; Table 1). Such a preparation method reads on step i) of the instant invention. The 10% solution of poloxamer-188 with ADM reads on the aqueous phase while the Lipiodol reads on the oily phase. As such, the emulsion comprises the copolymer surfactant at a concentration of 10% w/v of the aqueous phase. As already discussed, Lp-Em was injected into the hepatic artery in subjects with unresectable HCC, followed by TAE (p. 9, “clinical considerations” and “clinical applications of Lp-Em”). Such a method reads on step ii) of the instant invention. Lp-Em appeared to be an effective selective cancer chemotherapy for HCC (p. 11, “summary”).
Regarding claim 2: The emulsion is delivered via injection into the hepatic artery followed by TAE (p. 9, “clinical considerations” and “clinical applications of Lp-Em”), which reads on transarterial administration.
Regarding claims 4-5: The lipiodol emulsion comprises Adriamycin (p. 9, Table 1), also known as doxorubicin, which is a chemotherapeutic drug as evidenced by GoodRx.
Kodama further teaches that many anticancer drugs are water-soluble and when mixed with Lipiodol, early dissociation of the anticancer drug occurs, making it difficult to achieve sustained release. Therefore, it was hypothesized that sustained release of the anticancer drug could be achieved by emulsifying it with a surfactant (p. 8, “Introduction”).
The teachings of Kodama differ from that of the instantly claimed invention in that Kodama does not explicitly teach the copolymer surfactant at a concentration of about 20% w/v of the aqueous phase, as recited in claim 1.
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 adjust the amount of the copolymer surfactant in the emulsion to arrive at the instantly claimed amount of 20% w/v of the aqueous phase. While the 10% w/v taught by Kodama does not read on the instantly claimed amount it is well within the abilities of an ordinary artisan to optimize the amount of the copolymer surfactant in the aqueous phase depending on the desired release of the water soluble active and stability of the final emulsion. As such, one of ordinary skill in the art would have arrived at the instantly claimed amount through no more than routine experimentation. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Furthermore, it is taught by Kodama that the copolymer surfactant is responsible for the sustained release of the anticancer drug meaning its amount is a result effective parameter for the therapeutic method. The optimization of a result effective parameter is considered within the skill of the artisan. See, In re Boesch and Slaney (CCPA) 204 USPQ 215. This is what research chemists do, optimization of result-effective variables through routine experimentation (MPEP 2144.05 IIA and B).
One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification since Kodama teaches a method of preparing the emulsion and a starting point of 10% w/v, from which one of ordinary skill could have performed routine optimization.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kodama as applied to claims 1-2 and 4-5 above, and further in view of Huang D, et al. (2017). TACE plus percutaneous chemotherapy-lipiodol treatment of unresectable pedunculated hepatocellular carcinoma. Medicine (Baltimore). 96(30):e7650 (on record), hereinafter Huang.
The teachings of Kodama are discussed above, as are the rejections of claims 1-2 and 4-5.
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.
Claims 1-2 and 4-9 are rejected under 35 U.S.C. 103 as being unpatentable over Kodama as applied to claims 1-2 and 4-5 above, and further 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 (on record), hereinafter Komal.
The teachings of Kodama are discussed above, as are the rejections of claims 1-2 and 4-5.
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.
Response to Arguments
Applicant's arguments filed 07/16/2026 have been fully considered but they are not persuasive:
(1) Applicant objects to the use of Kodama as a reference, arguing that the machine translation is not of sufficient quality to be adequate evidence (p. 7 or Remarks).
Examiner apologizes for the poor quality and visibility of the document, however, this appears to be due to the scanning quality which Examiner is not responsible for. The text cited in the office action is clearly legible on the Examiner’s end and the instantly claimed invention is clearly taught by the reference. One would further recognize the references to “lipiodol”, “liviodur”, and “liviodol” as references to the lipiodol, which is a central component of the Kodama disclosure.
(2) Applicant further argues that Kodama does not teach the concentration of the copolymer surfactant as claimed. Applicant further asserts that 20% w/v of a copolymer surfactant provides the benefit of a 500-fold increase in stability compared to an emulsion without the copolymer surfactant (p 6-7 of Remarks).
While Kodama no longer anticipates the instantly claimed amount, such an amount would have been obvious to one of ordinary skill in the art given the reasons discussed above. In response to Applicant’s assertion of a 500-fold increase in stability, it is noted that the prior art differs from the claimed invention in the amount of the copolymer surfactant, not in the presence of it altogether. Thus, a 500-fold increase in stability when compared to a composition having no surfactant, is not a comparison to the closest prior art and does not show criticality in the instantly claimed amount. An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).
Conclusion
No claims 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 SUSANNAH S ARMSTRONG whose telephone number is (571)272-0112. The examiner can normally be reached Mon-Fri 9-5 (Flex).
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/SUSANNAH S ARMSTRONG/Examiner, Art Unit 1616
/ERIN E HIRT/Primary Examiner, Art Unit 1616
