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 .
Claims 1-2 are pending and under examination.
This is the First Office Action on the Merits of US Application 18/195,381 filed on May 10, 2023 which claims foreign priority benefit of CHINA 202210502745.2 filed on May 10, 2022. The Filing Receipt filed on 10/04/2024 is controlling. No English Language Translation of the CHINA 202210502745.2 is of record.
Information Disclosure Statement
The IDS filed on 06/01/2023 has been considered by the examiner. Please note that references not in the English language are considered only to their English language Abstracts as noted in the IDS by the examiner initials.
Claim Objections
Claim 1 is objected to because of the following informalities: The list of the six “wherein” clauses (“in S1”, a mass…) at the end of claim 1 appear to be missing the term “wherein”. Note that the wherein clause begins at the end of line 2 and ends in line 27. Also, claim 1, line 26, is missing the term “and” following the second to last term of this “wherein” clause list. Specifically, an “and” is needed at the end of line 26 after the term “in S4, a method for washing is centrifugal floating;”.
Also, the abbreviated term PBS in line 13 should be written in full-length the first time it appears in the claim.
Appropriate correction is required.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Han et al in BMP9‐induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus‐associated hepatocellular carcinoma (Clin Transl Med. published May 2, 2023: Vol 13(No5):e1247).
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the Han et al reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1).
Regarding claim 1, Han et al disclose a method of using a BMP9 in combination with an NK cell and a PD-L1 antibody in preparing a medicament for treating an HBV-positive liver cancer. (See Title, Graphical Abstract and FIG8 & legends).
Han et al teach that the BMP9 is loaded on a drug carrier and that the drug carrier is a drug carrier microbubble. (See Graphical Abstract and FIG8 & legends). In Section 3.6 Han et al disclose that “[a]nti-tumour activity is increased by combination therapy with NK cells and PD-L1 ICB targeting in BMP9-overexpresing HBV-infected HCC”. (See also Fig6 & legend). In Section 3.7, Han et al recite that “UTMD-mediated BMP9 delivery enhances the efficacy of immunotherapy”. See also Fig7 & legend). Further, regarding claim 1, steps (S1-S5), in Section 2.7 “Construction of BMP9-loaded microbubbles”, Han et al disclose a preparation of the BMP9-loaded microbubbles.
Regarding claim 1, S1: Han et al disclose dissolving 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-polyethylene glycol 2000 (PEG2000), and stearic acid-modified branched polyethylenimine-600 (Stearic-PEI600) in an organic solvent to obtain a first resulting mixture, and stirring the first resulting mixture for half an hour to give a phospholipid suspension. Further, Han et al disclose a mass ratio of the DSPC, the DSPE-PEG2000, and the Stearic-PEI600 is 82:9:9. (See Section 2.7, lines 1-2).
Regarding claim 1, S2: Han et al disclose uniformly mixing the phospholipid suspension, and removing the organic solvent from the phospholipid suspension to obtain a second resulting mixture. (See Section 2.7, left col, lines 1-4; right col. lines 1-2). Further, in S1 and S2, the organic solvent is a mixture of chloroform and methanol in a volume ratio of 9:1 (See Section 2.7, left col, lines 1-4).
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Regarding claim 1, S3, Han et al teach adding PBS in the second resulting mixture to obtain a resulting solution, and incubating the resulting solution in a 60 °C water bath for 15 min to obtain an incubated solution. (See Section 2.7, right col. lines 4-6).
Regarding claim 1, S4: Han et al teach shaking the incubated solution for 40 s in a bio-inert gas atmosphere, centrifuging the incubated solution to give an ultrasound microbubble, and washing the ultrasound microbubble to remove a phospholipid not forming the ultrasound microbubble. Han et al teach the bio-inert gas atmosphere is perfluoropropane (C3F8). (See Section 2.7, right col, lines 6-8). Further, in S4, Han et al teach a centrifugation condition is 400 g/min for 4 min and a method for washing is centrifugal floating. (See Section 2.7, right col, lines 9-16).
Regarding claim 1, S5: Han et al teach adding the BMP9 into a washed microbubble to obtain a third resulting mixture, and incubating the third resulting mixture for 1.5 h at room temperature to give a drug-carrying microbubble Further, in S5, Han et al teach an amount ratio of the BMP9 to the washed microbubble is 20 µg:108. (See Section 2.7, right col, lines 10-16 and Supplemental Material). MBs-BMP9 (BMP9-loaded microbubbles) (20ng/250µl, i.v.)
Regarding claim 2, Han et al disclose that the medicament is an agent configured for promoting a tumor cell death or killing tumor cells. (See Title; Graphical Abstract & legend; FIGS 6-8).
Thus Han et al anticipates claims 1-2.
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 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (US 2022/0305139 published 09/29/2022, filed on 09/01/2020, in view of Kim et al in PD-L1 Targeting Immune-Microbubble Complex Enhances Therapeutic Index in Murine Colon Cancer Models Pharmaceuticals (Pharmaceuticals 2021, published Dec 23 2020; Vol 14 No 1, pages:1-13), in view of Yang et al Focused Ultrasound Improves NK-92MI Cells Infiltration Into Tumors (Frontiers in Pharmacology 2019 Apr 18;10:326), in view of Liu et al Synergistic anti-tumor effect of anti-PD-L1 antibody cationic microbubbles for delivery of the miR-34a gene combined with ultrasound on cervical carcinoma (Am J Transl Res. 2021 Mar 15;13(3):988-100), in view of Yeh et al (US2019/0365895A1 published 12/05/2019) and Chen et al (US 20190177391), in view of Jung et al (“Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population” Oncotarget, 2016, Vol 7, No 45, pages 73754-73768), in view of Sheyn et al “Ultrasound-based nonviral delivery induces bone formation in vivo” (Gene Therapy 2008 Vol 15, pages 257-266), Naimark et al (WO- 2007/030534 published March 15, 2007), and Kilway et al (US2016/0058907).
Regarding claim 1, Kim et al (2022) disclose a microbubble drug carrier. Kim et al disclose an immune microbubble complex, and a use thereof as a drug carrier for treating tumors. Kim et al disclose that their immune-microbubble complex (IMC) includes “microbubbles to which an antibody is conjugated, in which the microbubbles have excellent stability and excellent antibody binding strength, and it was confirmed that, when the immune-microbubble complex is treated with high-intensity focused ultrasound (HIFU), an anti-tumor effect is significantly increased and an immune-enhancing effect is exhibited”. (See Abstract). Kim et al suggest that their immune-microbubble complex “is expected to increase the efficiency of delivering the conjugated antibody and be used in both diagnosis and treatment of cancer, and exhibit various functions in the field of immunotherapy, including a contrast effect, half-life improvement, improved drug delivery, a lymphocyte concentration effect, cancer immunotherapy and induction of immunotherapy using ultrasound”. (See Abstract). Regarding claim 1, Step 1: Kim (2022) discloses dissolving 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-polyethylene glycol 2000 (PEG2000) in a chloroform-based organic solvent to obtain a first resulting mixture, and stirring the first resulting mixture to give a phospholipid suspension. Kim (2022) disclose that the DSPC, the DSPE have a molar ratio of 9:1, 7:3, 6:4, 5:5, or 3:7. ((See ref claims 4-5; page 5, lines 4-5; page 24, lines 1-5).
Also, regarding claim 1, step S2: Lui et al and Kim (2022) each disclose uniformly mixing the phospholipid suspension, and removing the organic solvent from the phospholipid suspension to obtain a second resulting mixture. (See Kim 2022, page 24, lines 1-5). Regarding Step 1 and Step 2, Kim et al 2022 & Liu et al (Liu page 989: Preparation of targeted microbubbles) discloses the organic solvent is a mixture of chloroform and methanol in a volume ratio of 9:1.
Regarding claim 1, step S3: Kim 2022 disclose adding PBS in the second resulting mixture to obtain a resulting solution, and incubating the resulting solution in a 60 °C water bath for 15 min to obtain an incubated solution. (See page 24, lines 3-9). Also, see Liu et al (page 989, left col., using a 55°C water bath with steady stream of the bio-inert nitrogen gas to remove chloroform.)
Regarding claim 1, step S4: Kim 2022 discloses shaking the incubated solution for 45 s in a bio-inert gas atmosphere being sulfur hexafluoride gas, centrifuging the incubated solution to give an ultrasound microbubble, and washing the ultrasound microbubble to remove a phospholipid not forming the ultrasound microbubble.
However, Kim 20222 and Lui et al to not meet the exact ratio combinations and centrifuging times (for example, Kim 2022 disclose a 45 second rather than a 40 second spin). In view of the nature of the methods, it is considered that optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal ratio of elements and centrifugation parameters needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of labeling step protocol sequence would have been obvious at the time of applicant's invention. In addition Kim (2021) evidences that optimization of such parameters specifically for preparing microbubble complex drug carriers. Kim (2021) disclose developing an immune-microbubble complex drug carrier showing therapeutic efficacy of PD-L1 targeting protocols against CT26 colon tumors. For optimization of microbubbles, Kim (2021) disclose examining combinations of different phospholipid molecules at various molar ratios (Fig1). Based on their results the disclose that the (ratio of 9:1 DSPC to PEG2K-NHS gave the maximum microbubble production. (See page 2, Section 2.1).
Yang et al teach methods using Focused Ultrasound and microbubbles in combination with NK cells that improve NK-92MI cell infiltration into ovarian tumors. (See Title; Abstract; Fig1 & legend; Fig3 & legend; paragraph bridging pages 8-9). Yang et al show that biodistribution of NK-92MI in xenograft ovarian tumor model includes the liver (see page 4, Fig3). Yang et al disclose that the combination of Focused Ultrasound and microbubbles can improve NK-92MI cells’ infiltration into tumors. The combination of Focused Ultrasound and NK-92MI had better treatment effect compared to the PBS group. See Abstract, Fig1, below & legend: Ultrasound and NK-92MI had better treatment effect compared to the PBS group. See Abstract, Fig1, below & legend: Abstract, Fig1, below & legend: Ultrasound and NK-92MI had better treatment effect compared to the PBS group. See Abstract; Fig1, below.
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Lui et al disclose that microbubbles were prepared using a ratio of DSPC, DSPE-PEG-2000, and branched-chain polyetherimide-600 (PEI-600) dissolved in chloroform at 9:5:5 ratio. Also, Lui et al disclose DSPC, DSPE-PEG2000 and stearic acid-modified branched polyethylenimine-600 (Stearic-PEI600) in an chloroform organic solvent to obtain a first resulting mixture, and stirring the first resulting mixture for half an hour to give a phospholipid suspension. Further, regarding Step 1, Liu et al discloses a mass ratio of the DSPC, the DSPE-PEG2000, and the Stearic-PEI600 is 82:9:9.
Regarding claim 1, Step S5: adding the BMP9 into a washed microbubble to obtain a third resulting mixture, and incubating the third resulting mixture for 1.5 h at room temperature to give a drug-carrying microbubble;
Regarding claim 2, each of the Kim references, the Yang and Lui references disclose that the medicament is an agent configured for promoting a tumor cell death or killing tumor cells. (See Kim et al 2020 Abstract; Kim et al 2022 para bridging pages 30-31; Yang et al Abstract, Fig1; and Lui et al Title & Abstract).
However, regarding claim 1 Step 4, while Kim 2022 discloses the preparation of microbubble drug carriers uses bio-inert gas atmosphere specifically a sulfur hexafluoride gas, they do not specify perfluoropropane (perflurocarbon) as the type of bio-inert gas. Yeh et al disclose using perfluoropropane as a preferred type of bio-inert gas in the preparation of therapeutic microbubbles. It would have been obvious for one of ordinary skill in the art to substitute the a sulfur hexafluoride bio-inert gas of Kim 2022 for the perfluoropropane bio-inert gas of Yeh et al in a preparation of microbubble drug carriers because it is a substitution of similar elements (bio-inert gases) used for similar function (preparing microbubbles).
Further, regarding claim 1, steps 4-5, Chen et al US 20190177391 A1 discloses preparation of perfluoropropane microbubbles lipid-stabilized microbubbles in para 0254:
[0254] Lipid-stabilized microbubbles were made as previously described [Iliskovic, et al., 1997]. Briefly, 250 mg of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 50 mg of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine and 10% glucose were mixed with PBS and boiled in water until fully dissolved. Next 2 mg of plasmid DNA was mixed with 0.5 ml of ethyl alcohol and centrifuged at 10,000 g for 5 min. The supernatant fraction was removed, and the DNA pellet was placed in an incubator at 37° C. for 5 min to remove any remaining ethyl alcohol. The DNA was then added to 50 μl of Lipofectamine 2000 (1 mg/ml; Invitrogen, Carlsbad, Calif., USA) and mixed for 20 min. This mixture was added to 250 μl of liposome solution, 5 μl of 10% albumin and 50 μl of glycerol (10 mg/ml) in 1.5 ml vials, and placed on ice. The headspace of the vials was filled with perfluoropropane gas, and the vials were then shaken for 30 seconds at 4° C.
Further, regarding claim 1 Step 5, Chen disclose an amount ratio of the cargo to the washed microbubble is about 20 µg:108. For example, 5.2±0.3×109 microbubbles for 250±10 μg/ml equals about 25 ug cargo per 5.2 x 108 microbubbles. See para [0254] just below.
The mean diameter and concentration of the microbubbles were 1.9±0.2 μm and 5.2±0.3×10.sup.9 bubbles per ml, respectively. The concentration of plasmid carried by the microbubbles was 250±10 μg/ml.
Further, while the combination of the references of Kim et al (2022), Kim et al (2021), Yang et al and Lui et al disclose microbubble complexes that are drug carriers, in in combination with a PD-L1 antibody, and in combination with an NK cell (Yang et al), in preparing a medicament for treating/killing tumor cells and with biodistribution to the liver, they do not disclose using a BMP9 as a drug cargo in combination with an NK cell and a PD-L1 antibody. Note that the limitation in the preamble “for treating an HBV-positive liver cancer” is construed as an intended use. The fact that Yang et al show that biodistribution of NK-92MI in xenograft ovarian tumor model includes the liver (see page 4, Fig3) is construed to meet this limitation.
Jung et al discloses that recombinant Bone morphogenetic protein-9 (BMP9) is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population. (See title, abstract, entire article).
Further, each of the references of Sheyn et al, Naimark et al, and Kilway et al suggest loading BMP9 as the therapeutic cargo in a microbubble carrier.
Sheyn et al disclose combining microbubbles and recombinant human BMP-9 for therapeutic delivery to a subject for gene therapy.
Naimark et al discloses medical device stents for delivering a therapeutic agent. (See Abstract.) Naimark et al suggest using therapeutically-loaded microbubble drug carriers for such delivery. (See Abstract, para 00135.) Naimark et al suggest using BMP-9 as the therapeutic cargo to be delivered. (See para 00141, line 2.)
Kilway et al (in paragraph [0095]) disclose using BMP-9 as a therapeutic cargo carried by microspheres.
[0095] Such fillers include, but are not limited to, a hydroxyapatite in the form of hollow microspheres or biocompatible, biodegradable glass. The microspheres of hydroxyapatite could be used to contain and act as carriers for antibiotics. Other components of the composites that could be delivered within the hydroxyapatite microspheres include growth factors such as bone morphogenetic proteins (“BMPs), cartilage-derived morphogenic proteins (“CDMPs”), collagen, or small molecules that are being developed to promote bone growth through blood vessel formation. In one aspect, the growth factor is selected from the group consisting of TGFβ1, TGFβ2, TGFβ3, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, CDMP-1, CDMP-2, or CDMP-3.
The level of skill in the art was high, at the level of a PhD or MD research scientist, before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to prepare microbubble drug carriers using a BMP9 in combination with an NK cell and a PD-L1 antibody in preparing a medicament configured for treating a cancer including a cancer located in the liver for the rationale of the cited references to improve effectiveness of delivery of a therapeutic agent using microbubble carriers.
It would have been obvious to one of ordinary skill in the art to do such because Yang et al disclose that the combination of Focused Ultrasound and microbubbles can improve NK-92MI cells’ infiltration into tumors and Liu et al show a synergistic anti-tumor effect of anti-PD-L1 antibody cationic microbubbles for delivery of a therapeutic agent (see Title). Further, in view of the cited references, it would have been obvious to use BMP9 (aka GDF2, BMP-9, BMP9, HHT5, growth differentiation factor 2) as the type of therapeutic cargo because Jung et al discloses that recombinant Bone morphogenetic protein-9 (BMP9) is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population. (See title, abstract, entire article) and each of Sheyn et al, Naimark et al, and Kilway et al explicitly suggest using BMP-9 as a therapeutic agent carried by a microbubble complex.
In view of the high skill level in the art before the effective filing date of the presently claimed invention it is considered that one of ordinary skill in the art having the cited references would have had a reasonable expectation of success to combine the elements of the cited references to arrive at the presently claimed invention.
Conclusion
No claim is allowed.
Related prior art which may be applied in a future office action:
Li et al Tumor perfusion enhancement by ultrasound stimulated microbubbles potentiates PD-L1 blockade of MC38 colon cancer in mice (Cancer Lett. Feb 1, 2021: Vol 498: pages 121-129). Li et al teach use of microbubbles with PD-L1 to promote a tumor cell death and killing tumor cells. (See Title, Abstract). Li et al teach that the combination therapy of ultrasound stimulated microbubble cavitation (USMC) with PD-L1 antibody “enhanced tumor perfusion and tumor growth inhibition. Li et al suggest using microbubbles combined with PD-L1 for therapeutic attack of solid tumors. (See Abstract; page 128, right col., para 2).
Gong et al Comparison of sonication patterns and microbubble administration strategies for focused ultrasound-mediated large-volume drug delivery (IEEE Trans Biomed Eng. 2022 Oct 19;69(11):3449–3459).
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658