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 .
DETAILED ACTION
The examiner for this Application has changed. Please direct all future correspondence to Patent Examiner, Katriel B Kasayan, AU 1634. Additional contact information can be found at the end of this paper.
This action is in response papers filed March 9, 2026. A response to the restriction requirement filed on March, 9 2026, has been acknowledged.
Claims 1, 14-16, 27, 33-46 are currently pending. Claims 1, 14, 16, 27, 33, 35, 44, 45 and 46 are independent claims. Applicants’ election without traverse Group III (e.g. claims 35-46), drawn to an in vitro organotypic tumor microenvironment (TME) model culture system is acknowledged.
Claims 1, 14-16, 27, 33 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. The requirement for restriction between Groups I-III is maintained for reasons of record and the foregoing commentary, and hereby made FINAL.
Therefore, claims 35-46 are under examination to which the following grounds of rejection are applicable.
Priority
The instant application is a 35 U.S.C. 371 national stage filing of International Application PCT/US2021/062388 filed on December 8, 2021. The International Application claims priority to US Provisional 63/122,815, filed December 8, 2020.
Therefore, the earliest possible priority for the instant application is December 8, 2020.
Specification Objection
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 35-46 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.
Regarding claim 35, it is indefinite in its recitation of the term “said system” claim 2 as it lacks proper antecedent basis. The preamble recites “an in vitro organotypic tumor microenvironment model (TME) culture system”.
Moreover, in claim 35 line 3 it is indefinite in its recitation of the phrase “said population” as it lacks proper antecedent basis. Line 3 recites “an isolated population of cells”.
Regarding claim 37, it is indefinite in its recitation of the phrase “the population” as it lacks proper antecedent basis. Line 3 recites “an isolated population of cells”.
Claim 37 is vague and indefinite because they recite the phrase "derived from" and the metes and bounds of how a population of population of tumor epithelial cells, fibroblasts, and mesenchymal stromal cells can be "derived from" the claimed tissues and still meet the intended limitation of the claims are not clear. Without a clear statement of the process by which the starting material is derivatized, it is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization, especially since the claimed starting material encompasses tissues as diverse as a breast tumor, pancreatic tumor, ovarian tumor, prostate tumor, lung tumor, colon tumor, solid tumor, glioma, melanoma, myeloma, liver tumor, and kidney tumor.. This rejection could be overcome by substituting "isolated" for "derived" in the claim.
For the purpose of a compact prosecution the term “derived” recited in claim 37 has been interpreted as “obtained or isolated from.”
Claims 38-43 is indefinite in its recitation of the term “the culture system” in line 1 as it lacks proper antecedent basis. Claim 35 recites “an in vitro organotypic tumor microenvironment model (TME) culture system”.
Claims 39-41 are indefinite in their recitation of the term “the population of cells” as it lacks proper antecedent basis. Claim 35 recites “an isolated population of cells”.
Regarding claim 43, it is indefinite in its recitation of the phrase “tumor epithelial cells characterized by”. The term "characterized" is not defined by the claim. The specification does not provide any closed definition as to what is meant by “characterized by”. It is unclear if the phrase “characterized by” should be interpreted narrowly to encompass only materials that have a structure identical to the associated markers (e.g. EpCAM+/CD49fhigh/CD24high/CD61-) or if the phrase should be interpreted broadly to encompass materials which have a structure “similar” to the associated markers. The metes and bounds are not clearly set forth.
Moreover, claim 43 is indefinite in its recitation of the term “EpCAM+/CD49fhigh/CD24high/CD61-“ as it is unclear if the tumor epithelial cells broadly require the expression of all of the listed markers or just a singular marker. As such, the metes and bounds of the claim are indefinite.
Claims 43 is vague and indefinite because it recites the phrase "derived from" and
the metes and bounds of how a population of the population of tumor epithelial cells and mesenchymal cells can be "derived from" a breast tumor and still meet the intended limitation of the claim are not clear. As discussed above, it is not possible to know the metes and bounds of a "derivative"
because any given starting material can have many divergent derivatives depending on
the process of derivatization. This rejection could be overcome by substituting "isolated"
for "derived" in the claim.
Regarding claim 44, it is indefinite in its recitation of “macrophages” as it lacks proper antecedent basis. Claim 35 recites an isolated population of cells comprising tumor epithelial cells, mesenchymal stromal cells, and fibroblasts. It is unclear if the disclosed “macrophages” are an addition to the isolated population of cells in claim 35 or they were pre-existing within the culture system. Amending the claim to recite “further comprising macrophages” would obviate the rejection.
Claims 44, 45 and 46 are vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention. Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchinson, 69 USPQ 138.
Claim 36, 45 and 46 are rendered indefinite insofar that it depends on claim 35.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 35-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite the nature-based product drawn to an organotypic tumor microenvironment model comprising an isolated population of cells from comprising tumor epithelial cells, mesenchymal stromal cells, fibroblasts and immune cells from a tumor. MPEP 2106 sets forth the multistep process for determining subject matter eligibility.
In accordance with the MPEP § 2016, claimed found to recite a statutory subject matter (e.g., compositions of matter) (Step 1: YES) are the analyzed to determine if the claims recite any steps that equate to an abstract idea, law of nature, or natural phenomenon. Claims 35-43 are drawn to a culture system comprising cell populations that occur in nature within the tumor microenvironment. Specifically, the claims recite naturally occurring cell populations isolated from tumor microenvironment as taught by Neal et al. (Published: 2018. Cell. 2018 Dec 13;175(7):1972-1988.e16.). As such, the claims and art merely recite the isolation and maintenance of such naturally occurring cell populations outside of the body, and the culture system does not recite structural or functional characteristics that render the population markedly different from the naturally occurring tumor microenvironment from which the cells are obtained.
The claimed organotypic culture system differs from the naturally occurring tumor microenvironment only in that the recited cells have been isolated from the tumor and placed into culture.
MPEP 2106.04(c) states that if a claim includes a nature-based product that does not exhibit markedly different characteristics from its naturally occurring counterpart in its natural state, then the claim recites a “product of nature” exception, and requires further analysis in Step 2A Prong Two to determine whether the claim as a whole integrates the exception into practical application (Step 2A, Prong One: YES)
The judicial exception is not integrated into a practical application because they do not recite any elements in addition to the recited judicial exception. MPEP 2106.04(d), subsection III states that a judicial exception alone is not eligible subject matter; therefore, if there are no additional claim elements besides the judicial, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. As such, claims 35-43 are directed to a natural product with no additional elements to demonstrate the claims as a whole integrate the exception into practical application. (Step 2A, Prong 2: NO).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. MPEP 2106.05, subsection I states that additional elements in the claims must be evaluated to determine whether they amount to an inventive concept, which requires considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself. Any additional steps, such as isolating the cell populations from tumors, are no more than routine in the art and do not transform the nature of the claim to be something distinct from their naturally occurring counterpart. Hence. Because claims 35-43 do not contain additional elements to demonstrate the claims as a whole integrate the exception into a practical application, the claim simultaneously does not recite significantly more than the exception itself. Since there is no meaningful limitation in the claim that transforms the exception into a patent-eligible application, such that the claim does not amount to significantly more than the exception itself. Therefore, claims 35-43 are directed to a judicial exception without significantly more and does not have an eligible subject matter under 35 U.S.C. § 101 (Step 2B: NO).
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.
Claim(s) 35, 37, 38-42 and 44-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Neal et al. (Published: 2018. Cell. 2018 Dec 13;175(7):1972-1988.e16.) in view of Taniguchi et al. (Cited in IDS Filed: 11/21/2024. US Patent Pub.: US 20170285002 A1)
Regarding claim 35, Neal teaches that an in vitro organotypic tumor microenvironment model (pp. 1972, Abstract, “Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immune-oncology investigations within the TME and facilitate personalized immunotherapy testing.”) comprising tumor epithelial cells and tumor-infiltrating lymphocytes (pp. 1972, Abstract, “Here, an air-liquid interface (ALI) method propagated patient derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages).”). Further, Neal et al. teaches that in contrast to patient-derived tumor organoids (PDO), “fibroblast overgrowth did not occur in mouse ALI tumor cultures.” (page 1976, col. 1, para 2), supporting (PDO) from human patient tumors comprising tumor epithelial cells, endogenous immune stroma, and fibroblasts. Moreover, Neal et al. states “The immune and fibroblast stroma in both human and mouse organoids progressively decline over a 1- to 2-month period” (page 1983, col 1, last para).
Though Neal discloses epithelium en bloc with endogenous immune stroma. Neal does not explicitly teach the stroma in addition to cancer cells in the PDO comprises mesenchymal stromal cells.
Taniguchi teaches that mesenchymal cells not only improve the tissue microenvironment for organoid cultures, but also enhance expression of ECM proteins (para 0002, “A tumor microenvironment constructed by the interaction between cancer cells and various cells present in the neighborhood of the cancer cells (e.g., mesenchymal cells such as tumor-related fibroblasts and vascular endothelial cells, and inflammatory cells such as macrophages) has been found to play an important role in the treatment resistance of cancer.”; para 0052, “In many cases, cancer tissue has a portion called stroma, in addition to cancer cells. In the stroma, mesenchymal cells including fibroblasts…these cells are present to form a characteristic structure. This structure is called cancer microenvironment.”)
In view of the benefits of using mesenchymal cells from a portion of stroma in cancer tissue improving the tissue microenvironment for organoid cultures and enhancing expression of ECM proteins, it would have been obvious to modify the organotypic model of Neal to further comprise mesenchymal stem cells as they play a role in cancer resistance. Further, a skilled artisan would have an organotypic model to comprise mesenchymal stem cells as they are physiologically relevant to the tumor microenvironment of stroma of cancer tissue. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
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Regarding claim 37, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches en bloc ALI organoid culture (tumor+ stroma) from human lung ( p. 1977, Figure 3. H)
Regarding claim 38, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches that patient-derived organoids contained T-cells (pp. 1976, “Human PDOs contained CD3+ T cells (tumor-infiltrating lymphocytes [TILs]) integrally embedded in close proximity to tumor epithelium”).
Regarding claim 39, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches that the population of cells are syngeneic (pp. 1976, “ALI organoids were also robustly generated from mouse tumors implanted subcutaneously (s.c.) into syngeneic immunocompetent hosts: mouse B16 melanoma transduced with SIY peptide (Sivan et al., 2015) and mouse MC38 colon adenocarcinoma cells in syngeneic C57BL/6 mice, or A20 B cell lymphoma cells in syngeneic BALB/c mice”).
Regarding claim 40, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches that the population of cells are primary cells (pp. 1972, Abstract, “Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immunooncology investigations within the TME and facilitate personalized immunotherapy testing”; pp. 1976, “Human PDOs contained CD3+ T cells (tumor-infiltrating lymphocytes [TILs]) integrally embedded in close proximity to tumor epithelium”) .
Regarding claim 41, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Taniguchi teaches that the population of cells are human cells (Abstract, “It is also intended to provide a method for reconstituting human cancer tissue using primary human cancer cells that retain the properties of human tumor.”).
Regarding claim 42, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches that the population of cells are murine cells (pp. 1976, col 1, “ALI organoids were also robustly generated from mouse tumors implanted subcutaneously (s.c.) into syngeneic immunocompetent hosts: mouse B16 melanoma transduced with SIY peptide (Sivan et al., 2015) and mouse MC38 colon adenocarcinoma cells in syngeneic C57BL/6 mice, or A20 B cell lymphoma cells in syngeneic BALB/c mice”).
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Regarding claims 44 and 45, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Further, Neal teaches that the organotypic model comprises both macrophages and natural killer (NK) cells (Graphical Abstract, See Attached). Neal also teaches immunotherapy modelling for a candidate compound (anti-PD-1/Nivolumab) (pp. 1981, col 1, “The PDO preservation of primary tumor epithelium en bloc with native endogenous TILs affords an opportunity for in vitro human immunotherapy modeling. We thus investigated the functional human PDO response to anti-PD-1 within a clinically actionable 7-day time frame.”), and identifying a candidate compound as one that is capable of expanding T-cells through immune profiling (Fluorescence-Activated Cell Sorting) (pp. 1981, col 2, “Nivolumab extinguished PD-1 FACS signal on CD3+ T cells, indicating nivolumab saturation of TIL cell-surface PD-1 via antibody competition against the distinct anti-PD-1 monoclonal used in FACS.”). Neal states “Both anti-PD-1 and anti-PD-L 1 strongly increased CD8+ TILs per total organoid CD3+ TILs (page 1978, col. 2, last para).
However, Neal does not explicitly teach testing the effects of anti-PD-1 nivolumab on macrophages or NK cells.
It was known in the art to evaluate the effect of therapeutic agents on organotypic TME models through immune profiling techniques such as Fluorescence-Activated Cell Sorting (FACS), and extend this immune profiling technique to other immune cells such as macrophages and NK cells. Such immune profiling would be routinely used to assess changes in immune-cell populations in response to the anti-PD-1 Nivolumab of Neal. Further, a skilled artisan would have been motivated to assess markers associated with macrophage phenotype and NK-cell activity before and after administration of anti-PD-1 Nivolumab on Neal’s organoid model to determine the compounds effects on the tumor microenvironment with reasonable expectation of success.
Regarding claim 46, the combined teachings of Neal and Taniguchi render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches immunotherapy modelling for a candidate compound (anti-PD-1/Nivolumab) (pp. 1981, col 1, “The PDO preservation of primary tumor epithelium en bloc with native endogenous TILs affords an opportunity for in vitro human immunotherapy modeling. We thus investigated the functional human PDO response to anti-PD-1 within a clinically actionable 7-day time frame.”), and identifying a compound as one that is capable of expanding T-cells (pp. 1981, col 2, “Nivolumab extinguished PD-1 FACS signal on CD3+ T cells, indicating nivolumab saturation of TIL cell-surface PD-1 via antibody competition against the distinct anti-PD-1 monoclonal used in FACS.”).
***
Claim(s) 35 and 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Neal et al. (Published: 2018. Cell. 2018 Dec 13;175(7):1972-1988.e16.) in view of Taniguchi et al. (Cited in IDS Filed: 11/21/2024. US Patent Pub.: US 20170285002 A1), and in further view of Li et al. (Published: 2020. Stem cells international, 2020, 5847876).
With regard to claim 35, the combined teachings of Neal, and Taniguchi render obvious the claimed organotypic model, as iterated above in the 103 rejection the content of which is incorporated in claim 35. In particular, the combined teachings of Neal and Taniguchi disclose organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma said stroma comprising mesenchymal cells and fibroblasts. However, the combined teachings fail to disclose that the fibroblasts are immortalized.
Li teaches that replacing primary stromal cells with immortalized fibroblasts decreased the difficulty in isolating primary fibroblasts and improved organoid culture times (pp. 2 col 2, “Organoid culture was later optimized by replacing primary mouse lung stromal cells with immortalized MLg mouse lung fibroblasts (also known as CCL206), which overcame the difficulty of isolating primary mouse lung fibroblasts and shortened the length of organoid cultures to 1 week”). It would have been obvious to substitute the fibroblasts of Neal with the immortalized fibroblasts of Li, as they were known alternatives promoting shorter organoid-culture periods and eliminated the difficulty in culturing primary fibroblasts. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
***
Claim(s) 35, and 43, are rejected under 35 U.S.C. 103 as being unpatentable over Neal et al. (Published: 2018. Cell. 2018 Dec 13;175(7):1972-1988.e16.) in view of Taniguchi et al. (Cited in IDS Filed: 11/21/2024. US Patent Pub.: US 20170285002 A1) in further view and Faridi et al. (Published: 2018. Cytotechnology, 70(2), 625–639.).
With regard to claim 35, the combined teachings of Neal, and Taniguchi render obvious the claimed organotypic model, as iterated above in the 103 rejection the content of which is incorporated in claim 35. Moreover, Neal teaches en bloc ALI organoid culture (tumor+ stroma) from human lung ( p. 1977, Figure 3. H)
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Regarding claim 43, the combined teachings of Neal, Taniguchi and render obvious the claimed organotypic TME model of claim 35. Moreover, Neal teaches n bloc ALI organoid culture (tumor+ stroma) from human lung ( p. 1977, Figure 3. H)
However, the combined teachings of Neal and Taniguchi do not disclose PDO from breast cancer trumor.
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However, Faridi teaches that the mesenchymal cells, fibroblasts and epithelial cells are isolated and characterized from breast cancer tumor (Title, “Isolation and characterization of the primary epithelial breast cancer cells and the adjacent normal epithelial cells from Iranian women’s breast cancer tumors”; pp. 625, Abstract, “Thus, we isolated the epithelial and fibroblast cells from biopsy samples of patients with breast cancer based on differential centrifugation followed by culture in selective media.”; pp. 631, “Cells isolated from breast tissues were categorized according to the presence of the specific cell surface markers to distinguish the origin of the isolated cells as epithelial or mesenchymal stem cell”; pp. 633 col 2, “The isolated cells were immunophenotyped for four surface markers and characterized as epithelial or mesenchymal phenotypes.”). Further, Faridi teaches that the tumor epithelial cells have a tumor profile characterized by Ep/ CAM+ and CD24 (pp. 631, “The results indicate the presence of CD24 and EpCAM in the surface of all epithelial cells, while these cells lack CD44 and CD49f at the surface.”; FIG 3, see attached).
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights