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 .
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.
Claim Status
Claims 1-8, 10-11, 13, 15-16, 21, 23, 26-31 are currently pending and examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 63/252,268 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The earliest appearance of a therapeutic comprising CAR-T or CAR-NK cells appears in application 17/958,234. The earliest appearance of treating a cancer by administering a therapeutic agent deemed to be effective appears in the present application. Consequently, claim 11 is afforded an earlies priority date of 9/30/22.
Claim Interpretation
Claims 1-2 contain the limitation “optionally”. For examination purposes, these limitations are not considered in the patentability analysis.
Claim Rejections - 35 USC § 112
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 1-8, 10-11, 13, 15-16, 21, 23, 26-31 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.
The term “sufficient” in claim 1 is relative terms which renders the claim indefinite. The term “sufficient” 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 specification as originally filed indicates as paragraph [0076] that the cells may be cultured for a period of anywhere from two days to four weeks. The specification does not indicate if time periods out of this range may be considered “sufficient”.
Claim 1 contains the limitation “seeding a plurality of cancer cells on the surface”. It is unclear if this limitation is indicating that the cancer cells on seeded between the cell culture article and the polyelectrolyte layers, or if the cells are disposed on the polyelectrolyte layers. For examination purposes, the claims are interpreted as comprising the latter.
Claim 1 recites the limitation "the coated surface" in last line. There is insufficient antecedent basis for this limitation in the claim.
Claim 2 recites the limitation "the coated surface" in last line. There is insufficient antecedent basis for this limitation in the claim.
The term “effective” in claim 2 is a relative term which renders the claim indefinite. The term “effective” 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 specification as originally filed is entirely silent as to what may be considered “effective” or not.
Claim 28 contains the limitation, less than 1000 cells per cm2 on the substrate”. Claim 28 depends from claim 1 which indicates that the cells are seeded “on the surface”. It is unclear where the cells are seeded.
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.
Claim(s) 1-2, 5, 13, 15-16, 21, 26-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshikata et al., Enhancement of drug efflux activity via MDR1 protein by spheroid culture of human hepatic cancer cells. Journal of Bioscience and Bioengineering, Vol. 111, No. 5 (May 2011) pp. 590-593 (hereinafter Oshikata) in view of Richert et al., pH dependent growth of poly(L-lysine)/poly(L-glutamic) acid multilayer films and their cell adhesion properties. Vol 570, No. 1-2 (10 Oct 2004) pp. 13-29 (hereinafter Richert) and Dhiman et al., On-chip anticancer drug screening- recent progress in microfluidic platforms to address challenges in chemotherapy. Biosensors and Bioelectronics, Vol. 137 (15 July 2019) pp. 236-254 (hereinafter Dhiman).
Regarding claims 1-2, 29-30, Oshikata discloses methods of culturing human hepatic cancer cell (HepG2) spheroids and testing the efficacy of anticancer therapeutics thereon (Abstract). Oshikata discloses coating a polystyrene culture dish with poly-L-glutamic acid (PLGA) (Spheroid formation of HepG2 cells). HepG2 cells are seed on the culture dish and cultured under conditions such that they form spheroids (Spheroid formation of HepG2). The spheroids are then incubated with anti-cancer therapeutics, and evaluated for 50% inhibitory concentration (IC50) (Drugs, Assessment of IC50 of drugs). Oshikata explains that the IC50 of anti-cancer therapeutics differs significantly between spheroid cultures and monolayer cultures (Assessment of IC50 drugs, Figs. 5-7). Oshikata suggests that the disclosed methods may be useful for screening anti-cancer therapeutics for efficacy in cancer patients (Abstract, Assessment of IC50 drugs).
Regarding claims 5, 13, 31, Oshikata discloses treating the spheroids with doxorubicin hydrochloride, epirubicin hydrochloride, and 5-fluorouracil (Drugs, Assessment of IC50 of drugs).
Regarding claim 27, Oshikata discloses that the diameter of the spheroids is less than about 150 µm (Spheroid formation of HepG2 cells and doxorubicin uptake activity, Fig. 1).
Oshikata does not disclose that the substrate is composed of polyelectrolyte multilayers.
Richert discloses methods of culturing chondrosarcoma cells on a poly-L-lysine (PLL) and PLGA polyelectrolyte multilayer film (Abstract, Introduction). Richert explains that there is significant interest in developing biomaterial surface coatings which are able to enhance or resist cell adhesion (Introduction). Polyelectrolyte multilayers with alternate depositions of polyanions and polycations allow for tunable properties, including adhesiveness (Introduction). The PEM films may be coated on any kind of material, including PDMS, with any shape (Introduction). Richert discloses depositing layers of PLGA and PLL layer-by-layer on glass slides (Preparation of the polyelectrolyte multilayer coated glass slides for cell adhesion experiments). The films may be prepared with between 0 and 11 layer pairs of PGA/PLL on the substrate (Physico-chemical characteristics of the PEI-(PGA/PLL) films build at different pHs, Fig. 1). Richter further discloses seeding single chondrosarcoma cells onto the PEM films (Cell culture and micromanipulation experiments).
Regarding claim 15, Richert discloses that the layers of PLGA and PLL are formed using a layer-by-layer technique (Preparation of the polyelectrolyte multilayer coated glass slides for cell adhesion experiments).
Richter does not disclose that the films may have between 12 and 20 layers. However, as per MPEP § 2144.04 duplication of parts is considered a routine expedient requiring no more than ordinary skill in the art. Further, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art, but are close. See MPEP § 2144.05. Therefore, the claimed range of 12 to 20 layers is considered obvious in view of the teachings of Richert.
Regarding claim 16, 21, Richert explains that PEM films with a top layer of PLGA demonstrate poor cell adhesiveness, and films with a top layer of PLL demonstrate strong cell adhesiveness (Introduction, Survey of literature regarding cell adhesion studies on polyelectrolyte multilayer films, Table 1). Crosslinking a film may increase the cell adhesion properties (Survey of literature regarding cell adhesion studies on polyelectrolyte multilayer films, Table 1). Richert explains that the properties of the PLGA/PLL films may be finely tuned for a desired application (Conclusions).
Regarding claim 26, 28 , Richert discloses seeding 40 single chondrosarcoma cells on the substrate such that the cells adhere (Cell culture and micromanipulation experiments).
As both Oshikata and Richert are directed to methods of culturing cancer cells on a substrate coated with PLGA, it would have been obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would understand that the substrate of Richert could be used in the method of Oshikata as a simple substitution of one known substrate for another, with a reasonable expectation that cancer cell spheroids would be produced.
The combination does not disclose that the cancer cells may be from a fluid sample of a cancer patient and comprises circulating tumor cells.
Dhiman reviews in vitro models for anti-cancer therapeutic drug screening applications (Abstract). Dhiman explains that various types of tumor models, including 3D spheroids, may be used to study drug resistance, personalized therapy, cell migration, drug combinations, or perform multi-platform drug screening (Introduction, Section 2.2.1, Table 1). Cancer types which may be evaluated using these types of systems include brain, bone marrow, breast, colon, liver, lung, nasopharynx, ovary, pancreas, skin, urinary, vasculature, and circulating tumor cells (CTCs) (Introduction, Table 1). Anti-cancer therapeutics which have been tested using these platforms include chemotherapeutics (cytotoxic drugs), (Table 3).
Regarding claims 30-31, Dhiman further explains that humans and their cancers are heterogeneous, such that personalized medicine is highly desirable (Section 3.3). Dhiman suggests testing a specific tumor’s response to various drugs and administering effective therapies to the subject would be highly advantageous (Section 3.3, Summary and Conclusions, Future directions).
As each of the references is directed to culture of cancer spheroids, it would have been obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would understand that the CTCs disclosed by Dhiman could be used in the method of the combination as a simple substitution of one known cancer type for another, with a reasonable expectation that cancer cell spheroids would be produced.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshikata in view of Richert and Dhiman as applied to claims 1-2, 5, 13, 15-16, 21, 26-31 above, and in further view of Ishiguro et al., Establishment and characterization of an in vitro model of ovarian cancer stem-like cells with an enhanced proliferative capacity. Cancer Research, Vol. 76, No. 1 (2016) pp. 150-160 (hereinafter Ishiguro).
The combination does not disclose that the culture media comprises a ROCK inhibitor.
Ishiguro examines the effects of ROCK inhibitors on cancer cell spheroid formation (Abstract). Ishiguro discloses preparing cancer cell spheroids in a culture media containing the ROCK inhibitor Y27632 (Spheroid culture). Ishiguro explains that inclusion of Y27632 improves spheroid formation in both colon and ovarian cancer spheroids (Spheroid cells derived from human ovarian cancer show characteristics of CSCs).
As each of the references is directed to culture of cancer spheroids, it would have been obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to include a ROCK inhibitor in the culture media as disclosed by Ishiguro to improve spheroid formation by the cancer cells.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshikata in view of Richert and Dhiman as applied to claims 1-2, 5, 13, 15-16, 21, 26-31 above, and in further view of Tu et al., Surface modification of poly(dimethylsiloxane) and its applications in microfluidics-based biological analysis. Rev Anal Chem, 31(3-4) (2012) pp. 177-192 (hereinafter Tu).
Regarding claim 4, the combination does not disclose that the substrate comprises an absorbent polymer or that the absorbent polymer is certain polymers or derivatives thereof.
Tu reviews methods for surface modifications of poly(dimethylsiloxane) (PDMS) for cell-based applications (Abstract). Tu explains that PDMS membranes are non-toxic, easy to fabricate, and low cost, but require surface modifications for biological purposes (Abstract, Introduction). PDMS surface modifications generally fall into three categories gas phase processing, wet chemical methods, and combinations thereof (Introduction). Wet chemical methods generally encompass dynamic surface modifications, protein adsorption, layer-by-layer (LBL) deposition, silanization, and sol-gel coating (Wet chemical methods). Tu explains that LBL assembly involves the alternating layers of polyanions and polycations into multilayers (Wet chemical methods). Combined strategies involve combining gas phase processing and wet chemical methods, such as plasma treatment with LBL assembly (Combination of gas phase and wet chemical methods). In one embodiment, an air plasma-treated PDMS membrane is then layered with polyvinyl alcohol (PVA) and glycerol (Combination of gas phase and wet chemical methods). Tu explains that modified PDMS substrates are useful for a variety of biological applications, including cell culture, immunoassays, DNA hybridization, etc. (Applications of PDMS surface modification in biological analysis, Table 1). In some embodiments, the substrates may be used for culture or analysis of cancer cells (Applications of PDMS surface modification in biological analysis)
As both Tu and Richter are directed to methods of modifying surfaces, such as PDMS, for biological applications, including cancer cell culture, it would be obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would be motivated to combine the references as simple substitution of one known LBL coating with another (e.g., glycerol with PLL/PLGA), with the predictable result that cancer cells could be cultured on the substrate.
Claim(s) 6-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshikata in view of Richert and Dhiman as applied to claims 1-2, 5, 13, 15-16, 21, 26-31 above, and in further view of Aref et al., 3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Royal Society of Chemistry, Vol. 18 (2019) pp. 3129-3143 (hereinafter Aref).
Regarding claims 6-8, the combination does not disclose that the therapeutic agent is an immune checkpoint inhibitor.
Aref discloses methods of screening the response of tumor cell spheroids to immune checkpoint blockade therapy (immune checkpoint inhibitors) (Abstract). Aref discloses preparing a cell spheroid containing tumor, immune, and stromal cells and treating with each of the immune checkpoint inhibitors pembrolizumab, ipilimumab, RMP1-14, or combinations thereof (Preparation of MDOTS/PDOTS and ex vivo microfluidic 3D culture).
As Oshikata and Dhiman are directed to drug screening using cell spheroids, it would have been obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would understand that the immune checkpoint inhibitors used in Aref could be used in the method of the combination as a simple substitution of one known anti-cancer therapeutic for another, with a reasonable expectation that anti-cancer therapeutics could be successfully screened.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshikata in view of Richert and Dhiman as applied to claims 1-2, 5, 13, 15-16, 21, 26-31 above, and in further view of Dillard et al., A spheroid killing assay by CAR T cells. JoVE Cancer Research, (12 Dec 2018) DOI:10.3791/58785 (hereinafter Dillard).
Regarding claims 10-11 the combination does not disclose that the therapeutic agent is a therapeutic cell composition.
Dillard discloses methods of using cancer cell spheroids for screening of adoptive cell therapies (e.g., CAR-T cells) (Abstract). Dillard discloses preparing colorectal cancer cell spheroids on a poly-L-lysine-coated substrate and incubating with CD19 positive CAR T cells (Generation of spheroids from colorectal cancer cell line, Generation of CD19 CAR T cells, 3D tumor spheroid killing assay). Dillard explains that the disclosed protocol may be used as a fast and easy screening method for testing or various drugs and/or immunotherapies (Discussion).
As Oshikata and Dhiman are directed to therapeutic screening using cancer cell spheroids, it would have been obvious to one of ordinary skill in the art that the references could be combined. A skilled artisan would understand that the CAR-T cells of Dillard could be used in the method of the combination as a simple substitution of one known anti-cancer therapeutic for another, with a reasonable expectation that anti-cancer therapeutics could be successfully screened.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3-8, 10-11, 13, 16, 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 11,713,441 in view of Richert.
With respect to claim 1 of the present application, and claim 1 or the ‘441 patent, the claims are directed to a method of preparing a cell culture by providing a cell culture substrate comprising polyelectrolyte multilayers and an absorbent polymer, seeding patient-derived cancer cells on the substrate, and culturing to obtain 3D spheroids. The claims differ in that the present application requires that the present application requires that the polyelectrolyte multilayers be certain components. As discussed in the art rejections supra, Richert discloses methods of culturing chondrosarcoma cells on a poly-L-lysine (PLL) and PLGA polyelectrolyte multilayer film (Abstract, Introduction). A skilled artisan would understand that the specific polyelectrolyte multilayers of Richert could be used as a known polyelectrolyte multilayer substrate for cancer cell culture with a reasonable expectation of success.
With respect to claim 2 of the present application, and claim 2 of the ‘441 patent, the claims are directed to a method of evaluating a therapeutic cancer by preparing tumor spheroids as per claim 1, contacting the spheroids with a therapeutic agent, and determining the effectiveness of the therapeutic agent. The claims differ in that the ‘441 patent requires specific means for evaluating effectiveness which obviates the broader scope of the present application. Claims 3-8, 10-11, 13, 16, 21 of the present application correspond to claims 3-6, 8-10, 13, 17-19 of the ‘144 patent.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA D JOHNSON whose telephone number is (571)270-1414. The examiner can normally be reached Monday-Friday 8:00-4:00 CT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
Prosecution Insights