DETAILED ACTION
This office action is in response to applicant’s filing dated August 6, 2026.
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
Claims 14-25 and 27-30 are pending in the instant application. Acknowledgement is made of Applicant's amendments filed August 6, 2026. Acknowledgement is made of Applicant's amendment of claim 14; and cancelation of claims 1-13 and 26.
Priority
The present application is a 371 of PCT/EP2022/079388 filed on October 21, 2022, which claims benefit of foreign priority to ITALY 102021000027437 filed on October 26, 2021.
Drawings
Acknowledgement is made of the drawings received on August 6, 2026. These drawings are accepted.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
Claim Rejections - 35 USC § 103
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 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 14-18, 20-23, and 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over Pessina et al (WO 2018/193413 A1, cited in the IDS filed April 24, 2024) in view of Yeo et al (WO 2011/119988 A1, cited in the IDS filed April 24, 2024).
Regarding claims 14, 15, 23, and 27, Pessina teaches delivery system comprising fat tissue or derivatives thereof preferably loaded with molecules and/or drugs for use in the treatment of cancer (claims 1 and 10); wherein said tissue is micro-fragmented fat (claim 3); wherein said molecules/drugs are anti-cancer molecules including paclitaxel (claims 6 and 7). Pessina teaches the tissue-based system of the invention allows molecules and/or drugs administration in individuals (any animal) in need thereof; preferably, the molecules/drugs are delivered in the interested site, preferably the sick and/or the injured site (page 8, 2nd paragraph); the tissue-based delivery system is for local, parenteral, peritoneal, mucosal, dermal, epidermal, subcutaneous, transdermal, intramuscular, nasal, oral, topical, vaginal, rectal or intra-ocular administration (page 14, 6th paragraph; and the tissue-based delivery system of the invention, eventually loaded with the molecules/drugs as disclosed above, is preferably pre and/or post-operatory administration/application, preferably topical, intraperitoneal, subcutaneous, administration/application, preferably for preventing the cancer relapses, more preferably for metastatic tumors (page 15, 2nd paragraph). Thus, Pessina teaches a method of treating cancer comprising administering an effective amount of a tissue-based drug delivery system comprising micro-fragmented fat tissue (MFAT) and an anticancer agent, paclitaxel, to a patient in need of such treatment.
Pessina does not explicitly teach the cancer is liver cancer.
However, Yeo teaches a method of treating hepatocellular carcinoma (HCC) in an individual in need thereof comprising administering to the individual an effective amount of a composition comprising nanoparticles comprising a taxane and an albumin (claim 1); wherein the taxane is paclitaxel (claim 16). Hepatocellular carcinoma reads on liver cancer.
As such, Pessina teaches a method of treating cancer comprising administering an effective amount of a tissue-based drug delivery system comprising micro-fragmented fat tissue (MFAT) and an anticancer agent, paclitaxel, to a patient in need of such treatment, and since Yeo teaches a method of treating liver cancer comprising administering a drug delivery composition comprising paclitaxel, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer comprising administering a drug delivery system comprising micro-fragmented fat tissue (MFAT) and paclitaxel to treat liver cancer with an expectation of success, since the prior art establishes that paclitaxel is useful for treating liver cancer.
Regarding the limitation “wherein the tissue-based drug delivery system is locally injected at the tumor tissue site and releases in situ a therapeutically effective amount of the anticancer,” Pessina teaches the tissue-based delivery system of the invention, eventually loaded with the molecules/drugs as disclosed above, is administered/applied in combination (pre-post) radiotherapy and/or surgery; preferably the tissue-based delivery system of the invention, eventually loaded with the molecules/drugs as disclosed above, is applied on the interested area before surgery for example in order to reduce the tumor area to be removed and therefore, to make the surgery less traumatic (page 14, last bridge paragraph). Pessina teaches data demonstrate that LPG/LASP is able to release all along the tested days a pharmacological effective amount of the drug, the PTX in this case, in particular for the tested drug, an effective anticancer activity; therefore, LPG and/or LASP can be used to release an effective drug amount (very high dosage) in the tumour area for several days, in particular, by the in situ injection. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to inject the tissue-based delivery system comprising MFAT and paclitaxel directly into the liver tumor in view of the teachings of Pessina which teaches that applying the tissue-based delivery system comprising MFAT and paclitaxel on the interested area before surgery for example is useful to reduce the tumor area to be removed and make the surgery less traumatic and the drug delivery system releases an effective drug amount in the tumor area for days by in situ injection.
Regarding claim 18, Pessina teaches the fat tissue is micro-fragmented by a non-enzymatic procedure and therefore the fat of the present invention is more preferably non-enzymatic micro-fragmented fat (page 8, last paragraph).
Regarding claims 20-22, Pessina teaches the fat tissue of the present invention is preferably isolated from any animal, more preferably from humans; preferably said animal/human is healthy or cadaver (page 11, 4th paragraph); and preferably the micro-fragmented fat is autologous or heterologous (page 11, 5th paragraph).
Regarding claims 28 and 29, Yeo teaches the method of treating hepatocellular carcinoma comprising administering paclitaxel is useful for treating liver cell carcinomas wherein the HCC (hepatocellular carcinoma) is primary HCC, advanced HCC, or metastatic HCC [0017].
Regarding claim 30, Pessina teaches the tissue-based delivery system of the invention, eventually loaded with the molecules/drugs as disclosed above, is administered/applied in combination (pre-post) radiotherapy and/or surgery.
Taken together, all this would result in the method of claims 14, 15, 18, 20-23, and 27-30 with a reasonable expectation of success.
Regarding claims 16 and 17, Pessina teaches the micro-fragmented fat of the invention contains clusters of fat tissue having size ranging preferably from 10 to 5000 µm more preferably from 100 to 1500 µm, more preferably from 400 to 900 µm (page 9, 3rd paragraph).
Regarding claim 25, Pessina teaches the amount said molecules/drugs that can be loaded/primed into the delivering system of the invention ranges from 1 to 5 mg/ml of fat tissue (page 4, 2nd paragraph). MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Taken together, all this would result in the method of claims 16, 17, and 25 with a reasonable expectation of success.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Pessina et al (WO 2018/193413 A1, cited in the IDS filed April 24, 2024) in view of Yeo et al (WO 2011/119988 A1, cited in the IDS filed April 24, 2024) as applied to claims 14-18, 20-23, and 25-30 above, and further in view of Alessandri Giulio et al (Journal of Controlled Release, 2019; 302:2-18, cited in the IDS filed April 24, 2024).
Pessina and Yeo teach all the limitations of claim 19 (see above 103), except wherein the MFAT is devitalized micro-fragmented fat tissue (DMFAT).
However, Alessandri Giulio teaches fresh preparation of MFAT specimens and, surprisingly, even its devitalized MFAT (DMFAT) counterpart, a fat derivative obtainable through a simple freezing/thawing (F/T) procedure, were very effective in adsorbing and releasing significant amount of the anti-cancer molecule PTX; both MFAT and DMFAT loaded with PTX (MFAT-PTX; DMFAT-PTX) were able to kill many different human cancer cell lines in vitro when located nearby tumor cells, with an impressing long lasting anti-cancer activity (page 3, left, last full paragraph). Moreover, Alessandri Giulio teaches the use of both MFAT and DMFAT for local cancer treatment will open very interesting perspectives for autologous and even heterologous applications in a wide variety of human cancers including hepatic (page 16, left, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilized DMFAT as the MFAT in the tissue-based delivery system comprising MFAT and paclitaxel for use in a method of treating liver cancer comprising administering the tissue-based delivery system directly into the liver tumor suggested by Pessina and Yeo with a reasonable expectation of success, since the prior art teaches both MFAT and DMFAT loaded with PTX (MFAT-PTX; DMFAT-PTX) were able to kill many different human cancer cell lines in vitro when located nearby tumor cells, with an impressing long lasting anti-cancer activity and will open applications in a wide variety of human cancers including hepatic.
Taken together, all this would result in the practice of the method of claim 19 with a reasonable expectation of success.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Pessina et al (WO 2018/193413 A1, cited in the IDS filed April 24, 2024) in view of Yeo et al (WO 2011/119988 A1, cited in the IDS filed April 24, 2024) as applied to claims 14-18, 20-23, and 25-30 above, and further in view of Li et al (Chinese Journal of Cancer, 2009; 28(8) pp 1-7).
As set forth above, the combination of Pessina and Yeo suggest a method of treating liver cancer comprising administering an effective amount of a tissue-based drug delivery system comprising micro-fragmented fat tissue (MFAT) and an anticancer agent, paclitaxel, to a patient in need of such treatment. Moreover, Pessina teaches the anticancer agent includes sorafenib (claim 6). Pessina and Yeo do not explicitly suggest the combination of paclitaxel and sorafenib for treating liver cancer.
However, Li teaches sorafenib 1s the first multi-targeted anti-tumor small molecule drug for oral use, which inhibits both tumor growth and vascularization; SHARP was a phase III trial of Sorafenib for patients with primary HCC, published in ASCO annual meeting in 2007; it showed that compared to control, the overall survival time and median progression-free survival in treatment group were prolonged by 2.8 months and 2.7 months, respectively (page 2, left, 1st paragraph). Li teaches chemotherapy is one of the most important treatments for advanced HCC; at present, drugs widely used in the clinical practice are as follows: Adriamycin, cisplatin, mitomycin, 5-FU, as well as gemcitabine, irinotecan which are approved by SFDA in recent years; besides, increasingly more pre-clinical studies have been conducted to explore the therapeutic effect of oxaliplatin and paclitaxel on hepatocellular carcinoma; BEL-7402 cell (hepatocarcinoma cell line) is relatively sensitive to paclitaxel and oxaliplatin, indicating those two drugs may become new choices for hepatocellular carcinoma in the future (page 3, right, 2nd paragraph); sorafenib alone and Sorafenib in combination with TAX on human hepatocellular carcinoma; sorafenib can induce apoptosis in BEL-7 402 cells, and administration of sorafenib after paclitaxel induces a higher apoptotic rate than administration before or simultaneously with paclitaxel (page 6, left bridge paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the method of treating liver cancer comprising administering an effective amount of a tissue-based drug delivery system comprising micro-fragmented fat tissue (MFAT) and an anticancer agent, paclitaxel, to a patient in need of such treatment to further contain sorafenib in the drug delivery system with a reasonable expectation of success, since the prior art teaches sorafenib is useful for treating hepatocellular carcinoma and sorafenib can induce apoptosis in hepatocarcinoma cells and administration of sorafenib after paclitaxel induces a higher apoptotic rate than administration before or simultaneously with paclitaxel.
Taken together, all this would result in the practice of the method of claim 24 with a reasonable expectation of success.
Response to Arguments
Applicant argues:
Despite the known resistance of HCC tumor cells to paclitaxel, the MFAT/DMFAT delivery system was able to overcome that limitation. The inventors demonstrated for the first time that both fresh MFAT and its devitalized counterpart (DMFAT), loaded with paclitaxel (PTX), are highly effective in inhibiting the growth of the HCC tumor cell line Hep-3B in vitro. Although Pessina already disclosed MFAT as a drug-delivery platform and paclitaxel as one of the potential drugs that could be loaded into the platform, it was not predictable that an MFAT- or DMFAT-based delivery system loaded with paclitaxel would be effective against HCC, particularly in view of the known resistance of HCC cells to paclitaxel.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 2143.02 states:
Conclusive proof of efficacy is not required to show a reasonable expectation of success.
Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018
(Fed. Cir. 2018). Absolute predictability is not a necessary prerequisite to a case of obviousness.
Rather, a degree of predictability that one of ordinary skill would have found to be reasonable
is sufficient. The Federal Circuit concluded that "[g]ood science and useful contributions do not
necessarily result in patentability." Id. at 1364, 83 USPQ2d at 1304.
In the instant case, as set forth above, Pessina teaches a method of treating cancer comprising administering an effective amount of a tissue-based drug delivery system comprising micro-fragmented fat tissue (MFAT) and an anticancer agent, paclitaxel, to a patient in need of such treatment. As set forth above, Yeo teaches a method of treating liver cancer comprising administering a drug delivery composition comprising paclitaxel, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer comprising administering a drug delivery system comprising micro-fragmented fat tissue (MFAT) and paclitaxel to treat liver cancer with an expectation of success, since the prior art establishes that paclitaxel is useful for treating liver cancer.
Applicant argues:
In vivo studies further showed that a single administration of DMFAT-PTX placed near the HCC tumor site produced an especially strong inhibitory effect on tumor growth. The pharmacokinetic data in the specification further reinforce the unexpected nature of these findings. The data suggest that the presence of the tumor nodule initially accelerated the release of PTX from DMFAT when the two were located in close proximity. An equilibrium PTX concentration between DMFAT and the tumor was reached within approximately 48 hours, and pharmacologically relevant PTX levels remained detectable in the tumor for at least seven days. These results provide strong evidence that the claimed invention achieves an effect that would not have been predicted from either Pessina or Yeo or from a combination thereof.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Pessina teaches the time releasing kinetics of LPG/PTX (paclitaxel in micro-fragmented fat tissue) at different times of incubation (1, 2, 3, 5, and 7 days) (page 18, 3rd paragraph); the results show that the total amount of PTX released at day 1 is 60.9 ng for LPG/PTX and at day 7 it is 175.7 ng for LPG/PTX (page 21, last paragraph). Thus, it is not unexpected that PTX levels remain detectable in liver tumor for at least seven days.
Applicant argues:
It should be noted that Yeo acknowledged the limitations of conventional paclitaxel in treating HCC. While Yeo may demonstrate that its specific nanoparticle albumin formulation can be effective against HCC, there is no reason to expect that a completely different delivery platform, namely the MFAT-based platform disclosed in Pessina, would likewise overcome the known resistance of HCC to conventional paclitaxel. In particular, MFAT and albumin are not alternative versions of the same platform. Rather, MFAT and albumin are fundamentally different delivery platforms. Albumin is generally considered to be a soluble molecular carrier whose primary role is to improve drug pharmacokinetics, biodistribution, and systemic transport. By contrast, MFAT is a structurally preserved adipose tissue containing extracellular matrix and stromal-vascular niche components. These components may function as a localized biological "bioreactor" or tissue reservoir. There is an important distinctions between (i) a circulating molecular carrier requiring association of the drug, as with albumin and (ii) a localized tissue-based reservoir into which the drug may simply be incorporated, as in MFAT of DMFAT. In view of that distinction, a person of ordinary skill would not expect comparable results for the two very different types of platforms.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
In response to applicant's argument that MFAT and albumin are different delivery systems, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As set forth above, Pessina teaches a method of treating cancer comprising administering an effective amount of a tissue-based drug delivery system comprising micro-fragmented fat tissue (MFAT) and an anticancer agent, paclitaxel, to a patient in need of such treatment. As set forth above, Yeo teaches a method of treating liver cancer comprising administering a drug delivery composition comprising paclitaxel, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating cancer comprising administering a drug delivery system comprising micro-fragmented fat tissue (MFAT) and paclitaxel to treat liver cancer with an expectation of success, since the prior art establishes that paclitaxel is useful for treating liver cancer. Yeo establishes that it was known in the art paclitaxel is useful for treating liver cancer and that delivery systems for insoluble drugs including paclitaxel are useful in methods of treating liver cancer. Moreover, Alessandri (cited in the previous Office Action) teaches MFAT used as a scaffold to deliver paclitaxel improves local drug concentration and prolongs therapeutic activity (abstract) and the level of PTX found in liver and kidney was higher (3,6–5,2 fold) when DMFAT-PTX was inoculated i.p. than that administrated s.c. (page 14, left, last paragraph). Thus, Alessandri establishes that it was known in the art that MFAT delivery system is bioavailable in the liver when administered i.p. The skilled artisan would have a reasonable expectation that MFAT-PTX would be delivered into the liver when administered locally to the liver in situ, since systemic delivery of MFAT-PTX results in delivery of PTX to the liver.
Conclusion
Claims 14-25 and 27-30 are rejected.
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628
