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
This action is in response to the papers filed November 7, 2023.
Claim Amendments
Applicant’s amendment to the claims filed 11/07/2023 is acknowledged.
Claims 20 and 22 have been cancelled.
Claims 1-19 and 21 are pending and under examination.
Sequence Compliance
Appropriate action is required so that the sequences disclosed in the specification comply with the sequence rules as discussed in MPEP 2421, MPEP 2422, and 37 CFR 1.821 through 1.825. The following sections of the specification fail to comply with the sequence rules:
The primer sequences disclosed in the Tables on pages 30 and 45 of the specification.
The sequence rules embrace all unbranched nucleotide sequences with ten or more nucleotide bases and all unbranched, non-D amino acid sequences with four or more amino acids, provided that there are at least 10 "specifically defined" nucleotides or 4 "specifically defined" or amino acids. The rules apply to all sequences in a given application, whether claimed or not. All such sequences are relevant for the purposes of building a comprehensive database and properly assessing prior art. It is therefore essential that all sequences, whether only disclosed or also claimed, be included in the database. See MPEP 2421.02.
Applicant should carefully review the entire specification to ensure compliance with the sequence rules. Applicant should provide a corresponding sequence identifier (SEQ ID NO) with every appearance of a sequence embraced by the sequence rules. If a sequence embraced by the sequence rules is lacking a corresponding sequence identifier (SEQ ID NO) in the instant Sequence Listing, Applicant should provide the sequence in a substitute computer readable form (CRF) copy and a substitute paper copy of the Sequence Listing, as an amendment specifically directing its entry into the application. Applicant should also provide a statement that the content of the paper and computer readable copies are the same and, where applicable, include no new matter, as required by 37 C.F.R.1.821(e) or 1.821(f) or 1.821(g) or 1.825(b) or 1.825(d). Applicant should provide a statement indicating any changes made to the Sequence Listing. Appropriate action is required in reply to this Office action. See attached PTO-2301.
Priority
The instant application 18/289,881 was filed on 11/07/2023. This application is a national stage of international application PCT/US2022/029869 filed 05/18/2022, claiming priority based on U.S. Provisional Application No. 63/190,147 filed 05/18/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/07/2023 has been considered.
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, or by applicant in an information disclosure statement (IDS), they have not been considered.
Claim Objections
Claims 11, 16-17 and 21 are objected to because of the following informalities:
In claim 11, line 3, the phrase “pneumoniae; Chlamydia psittaci; Coxiella burnetiid; Legionella pneumophila, Staphylococcus aureus; or” should be “pneumoniae, Chlamydia psittaci, Coxiella burnetiid, Legionella pneumophila, Staphylococcus aureus, or” instead.
In claim 16, the term “TGF-b” should be “TGF-β” instead.
In claim 17, line 2, the phrase “tissue’ and” should be “tissue; and” instead.
In claim 21, line 2, the phrase “imaging; quantitative RT-PCR; spatial” should be “imaging, quantitative RT-PCR, spatial” instead.
Appropriate action is required.
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 1-19 and 21 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.
In this case, there is a missing conjunction, e.g., “and/or” statement, between the steps in the process according to claim 1. Therefore, it is unclear whether the steps are recited in combination (i.e., an “and” statement) or in the alternative (i.e., an “or” statement).
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim 12 is 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.
In this case, there is a missing conjunction, e.g., “and/or” statement, between the steps in the process according to claim 12. Therefore, it is unclear whether the steps are recited in combination (i.e., an “and” statement) or in the alternative (i.e., an “or” statement).
Claim 9 is 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.
Claim 9 recites the virus is “human coronavirus including SARS-CoV1 and SARS-CoV2”. The phrase “including” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Amending claim 9 to recite “human coronavirus, SARS-CoV1, SARS-CoV2” would be remedial.
Claim 12 is 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.
Claim 12 recites a process step of “removing organoids from extracellular matrix culture.” The recitation is found to be indefinite. First, it is unclear if “removing organoids” refers to removing the organoids previously recited in the claims or any other organoid. Second, it is unclear if “extracellular matrix culture” refers to the culture medium comprising extracellular matrix previously recited in the claims or another culture composition. In sum, the lack of a clear nexus between the limitation of claim 12 and those previously recited in the claims creates a general lack of clarity regarding the metes and bounds of the claims.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Amending claim 12 to recite “removing the organoids from the culture medium comprising extracellular matrix” would be remedial.
Claim 21 is 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.
Claim 21 recites the step of analyzing the organoid is done by “microscopy, including fluorescence microscopy and staining”. The phrase “including” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Amending claim 21 to recite “microscopy, fluorescence microscopy, staining” would be remedial.
Claim Rejections - 35 USC § 102
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 1-9, 13, 17-18 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2014/0302491 A1 to Nadauld et al.
Nadauld discloses a method for the ex vivo culture, proliferation and expansion of primary tissue organoids. The cultures are initiated with fragments of mammalian tissue (i.e., explants), which are embedded in a gel substrate that provides an air-liquid interface. See, Abstract; par. 5, 30.
The tissues include lung alveolar tissue. See, Abstract; par. 5, 55. In the working examples, the lung alveolar tissue cultures are described as having bronchiolar and alveolar architecture. See, par. 15, 148-149.
The gel substrate is a semi-solid extracellular matrix. See, par. 29. Culturing conditions include a medium in which the cell are cultured, and any growth factors or differentiation-inducing factors that may be present. See, par. 43.
The cultured explants are continuously grown for a long term, while maintaining features of the tissue including prolonged tissue expansion with proliferation, multilineage differentiation, and recapitulation of the in vivo cellular and tissue ultrastructure, including epithelial tissues, submucosal tissues, and stromal environments. See, Abstract; par. 5.
Therefore, Nadauld is found to disclose a method for culturing organoids with distal lung alveoli and bronchioles en bloc with other natively present cell types, including stromal elements, as a cohesive unit without artificial reconstitution, comprising:
initiating a culture with a fragment of distal lung tissue; and
culturing the cells in a 3D air-liquid interface with a culture medium comprising extracellular matrix and an effective concentration of factors, for a period of time sufficient to form organoids comprising alveolar and terminal bronchiolar cells and other natively present cell types, including stromal cells.
Claim 1 further recites that the tissue culture contains endogenous immune cells, mesenchymal cells, and stromal cells. Nadauld discloses that the tissue culture contains varied cells found in normal mammalian tissues and recapitulates the cellular and tissue ultrastructure, including stromal environments. However, Nadauld does not expressly identify endogenous immune cells and mesenchymal cells in the tissue culture.
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). See, MPEP 2112.
In this case, the limitation wherein the tissue culture contains endogenous immune cells, mesenchymal cells, and stromal cells describes an intended result or functional property of performing the process steps (manipulative actions) positively recited in claim 1. A recitation of an intended result or functional property of the claimed process must result in a manipulative difference between the claimed process and the cited prior art in order to patentably distinguish the claimed process from the cited prior art. If the prior art process is capable of performing the intended result, or if the functional property naturally flows from the prior art process, then the prior art reads on the intended result or functional property recitation. There is no requirement that the cited prior art expressly teach or suggest the intended result or functional property recitation, but only that the subject matter is, in fact, present in the cited prior art. As outlined above, the manipulative actions positively recited by the claims are anticipated by the cited prior art. In particular, Nadauld teaches the process steps of initiating a culture with a fragment of distal lung tissue, ad culturing the cells in a 3D air-liquid interface with a culture medium comprising extracellular matrix and an effective concentration of factors for a period of time sufficient to form organoids having bronchiolar and alveolar architecture, without artificial reconstitution, as claimed in claim 1. Therefore, the intended result or functional property of wherein the tissue culture contains endogenous immune cells, mesenchymal cells, and stromal cells would have naturally flowed from performing the process steps taught by Nadauld. Moreover, Nadauld expressly teaches that the tissue culture contains varied cells found in normal mammalian tissues and recapitulates the cellular and tissue ultrastructure including stromal environments, which fairly suggests that cell types natively present in distal lung tissue, such as immune cells, mesenchymal cells and stromal cells, are also present in the tissue culture. Accordingly, absent evidence to the contrary, the intended result or functional property recitations are not found to patentably distinguish the claimed invention from the cited prior art.
For these reasons, Nadauld anticipates the process of claim 1.
Regarding dependent claims 2-5, the claims further recite the organoids comprise lung epithelial, mesenchymal and immune cells (claim 2); the epithelial cells comprise E-cadherin+ epithelial cells, SFTPC+ AT2 cells, KRT5+ basal cells, SCGB1A1+ club cells, tubulin+ cilia cells, and HT1-56+ AT1 cells (claim 3); the immune cells comprise CD4+ T cells, CD8+ T cells, B cells, and macrophages (claim 4); and the mesenchymal cells are vimentin+ mesenchymal cells (claim 5).
These limitations describe intended results or functional properties that naturally flow from performing the process steps (manipulative actions) positively recited in claim 1. Therefore, for the same reasons provided above with regards to claim 1, the intended result or functional property recitations of dependent claims 2-5 are not found to patentably distinguish the claimed invention from the cited prior art.
Regarding dependent claim 6, Nadauld teaches that the mammalian tissue is human tissue. See, par. 34.
Regarding dependent claims 7-9, Nadauld teaches that the organoid is infected with an adenovirus. See, e.g., par. 16, 88.
Regarding dependent claim 13, Nadauld discloses that the tissue cultures can be continuously grown for an extended period of time, e.g., for 1 month or more, e.g., for a year or more. See, Abstract, par. 5.
Regarding dependent claims 17-18, Nadauld discloses that the tissue cultures (organoids) find use in many applications, including disease modeling and drug discovery (par. 5). For example, the cells may be exposed to viral or bacterial pathogens to develop a reagent for experiments assessing the anti-viral or anti-bacterial effects of therapeutic agents (par. 80). Diseases that can be modeled in vitro using lung alveolar organoids include viral, bacterial or fungal infection (par. 55).
Methods of screening candidate agents for anti-viral or anti-bacterial activity are disclosed, wherein the candidate agent’s ability to inhibit or neutralize a biologically active pathogen is assessed. The organoids are contacted with the agent of interest in the presence of a bacterial, viral or fungal pathogen and the effect of the agent is assessed by monitoring one or more output parameters, such as cell survival / viability, explant growth, etc. See, e.g., par. 84, 103, 111-112.
Regarding dependent claim 21, Nadauld discloses a step of analyzing the organoid by, e.g., microscopy, histology, staining, etc. See, e.g., par. 78, 117.
For these reasons, dependent claims 2-6, 13, 17-18 and 21 are also anticipated by Nadauld.
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.
Claims 10-11 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2014/0302491 A1 to Nadauld et al., as applied to claims 1-9, 13, 17-18 and 21 above.
Regarding dependent claims 10-11, Nadauld teaches that the lung alveolar organoids are used as an in vitro model of viral or bacterial infection (par. 55), and the organoids are contacted with the agent of interest in the presence of a viral or bacterial pathogen to assess the effect of the agent on one or more output parameters of the organoid (par. 84, 103, 111-112).
Nadauld does not teach that the bacterial pathogen is a respiratory pathogen, as claimed in claim 10, or one of the species of bacteria recited in the Markush grouping of claim 11.
However, prior to the effective filing date of the instantly claimed invention, Mycobacterium tuberculosis was a known respiratory pathogen that infects lung tissue (Official Notice taken, if necessary). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Nadauld by infecting the tissue with Mycobacterium tuberculosis, as previously known in the art, with a reasonable expectation of success because Nadauld teaches the lung alveolar organoids are useful to model bacterial infection, and infecting the organoids with Mycobacterium tuberculosis would have provided a tool to study respiratory infection by the pathogen.
For these reasons, dependent claims 10-11 would have been prima facie obvious over Nadauld.
Regarding dependent claim 19, Nadauld teaches methods of screening candidate agents for anti-viral or anti-bacterial activity are disclosed, wherein the candidate agent’s ability to inhibit or neutralize a biologically active pathogen is assessed. The organoids are contacted with the agent of interest in the presence of a bacterial, viral or fungal pathogen and the effect of the agent is assessed by monitoring one or more output parameters, such as cell survival / viability, explant growth, etc. See, e.g., par. 84, 103, 111-112.
Nadauld does not teach that the agent is a vaccine, as claimed by claim 19.
However, prior to the effective filing date of the instantly claimed invention, vaccines were a known anti-viral agent and therapeutic for viral infection (Official Notice taken, if necessary). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Nadauld by contacting the tissue culture with a vaccine, as previously known in the art, with a reasonable expectation of success because Nadauld teaches the tissue cultures are useful for screening anti-viral agents, and contacting the tissue cultures with a vaccine would have provided a means of assessing the pharmacological properties of the vaccine in an in vitro environment.
For these reasons, dependent claim 19 also would have been prima facie obvious over Nadauld.
Claim 12 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2014/0302491 A1 to Nadauld et al., as applied to claims 1-9, 13, 17-18 and 21 above; in further view of Co et al. (2019) “Controlling epithelial polarity: a human enteroid model for host-pathogen interactions” Cell reports, 26(9), 2509-2520.
Nadauld does not disclose that the organoids are everted by removing the organoids from the culture medium comprising extracellular matrix, and placing the organoids in suspension culture, thereby leading to relocation of differentiated cells from the lumen to the exterior of the organoid.
Co is relevant prior art for teaching a method of making organoids derived from gastrointestinal tissue (enteroids) to study pathogen-epithelial interactions. Co developed a technique to reverse organoid polarity such that the apical surface everts to face the culture media, providing access to the apical surface. The process comprises removing the organoids from a culture medium comprising extracellular matrix, and placing the organoids in suspension culture. See, e.g., Abstract; Fig. 1; and pg. 2510-2511, joining paragraph.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Nadauld by everting the organoids through a process of removing the organoids from the culture medium comprising extracellular matrix, and placing the organoids in suspension culture, as taught by Co, with a reasonable expectation of success because eversion provides exogenously-introduced pathogens access to the apical surface.
Claims 1-9, 13-17 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0119107 A1 to Neal et al.; in view of US 2014/0302491 A1 to Nadauld et al.
Neal discloses methods for in vitro culture systems of human solid tumors as 3-dimernesionla (3D) patient-derived organoids (PDOs) that recapitulate the cellular architecture and ultrastructure of the tumor sample from which they were derived, and include immune cells, such as tumor infiltrating lymphocytes, and parenchymal and stromal elements. The cultures provide screening assays to predict a patient’s response to cancer therapies, including immunotherapies. See, Abstract, par. 10.
The cultures are initiated with fragments of solid tumor tissue (explants), which are then cultured embedded in a gel substrate that provides an air-liquid interface, for a period of time sufficient to form organoids. The gel substrate is a semi-solid extracellular matrix. The medium is supplemented with an effective concentration of factors to support the tissue culture. See, par. 12, 23-25.
The tissue sample is lung tissue, and the cancer is lung cancer. See, par. 20, 63, 91, 93.
Therefore, Neal is found to disclose a method for culturing organoids of lung tissue en bloc with infiltrating endogenous immune cells and stromal cells as a cohesive unit without artificial reconstitution, comprising:
initiating a culture with a fragment of lung tissue; and
culturing the cells in a 3D air-liquid interface with a culture medium comprising extracellular matrix and an effective concentration of factors, for a period of time sufficient to form organoids comprising lung cells and endogenous immune and stromal cells.
Neal does not teach that the lung tissue is distal lung tissue, as claimed in claim 1.
Nadauld is relevant prior art for teaching a method for the ex vivo culture, proliferation and expansion of primary tissue organoids. The cultures are initiated with fragments of mammalian tissue (i.e., explants), which are embedded in a gel substrate that provides an air-liquid interface. See, Abstract; par. 5, 30. The cultured explants are continuously grown for a long term, while maintaining features of the tissue including prolonged tissue expansion with proliferation, multilineage differentiation, and recapitulation of the in vivo cellular and tissue ultrastructure, including epithelial tissues, submucosal tissues, and stromal environments. See, Abstract; par. 5.
Nadauld further teaches the mammalian tissue is lung alveolar tissue. See, Abstract; par. 5, 55. In the working examples, the lung alveolar tissue cultures are described as having bronchiolar and alveolar architecture. See, par. 15, 148-149. The tissue culture (organoids) find use in many applications, including disease modeling and drug discovery. Diseases that can be modeled in vitro using lung alveolar organoids include lung cancers. See, par. 5, 55, 104-105.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Neal by initiating the culture with a fragment of distal lung tissue, as taught by Nadauld, with a reasonable expectation of success because Nadauld was able to recapitulate the in vivo cellular and tissue ultrastructure of distal lung tissue, including the bronchiolar and alveolar architecture, and distal lung organoid would possess utility in screening assays for immunotherapies against cancers of the distal lung.
Claim 1 further recites that the tissue culture contains endogenous immune cells, mesenchymal cells, and stromal cells. Neal discloses that the tissue culture recapitulates the cellular architecture and ultrastructure of the tumor sample from which they were derived, and include immune cells, such as tumor infiltrating lymphocytes, and parenchymal and stromal elements. Nadauld discloses that the tissue culture contains varied cells found in normal mammalian tissues and recapitulates the cellular and tissue ultrastructure, including stromal environments. However, Neal does not expressly identify endogenous mesenchymal cells in the tissue culture, and Nadauld do not expressly identify endogenous immune cells and mesenchymal cells in the tissue culture.
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). See, MPEP 2112.
In this case, the limitation wherein the tissue culture contains endogenous immune cells, mesenchymal cells, and stromal cells describes an intended result or functional property of performing the process steps (manipulative actions) positively recited in claim 1. A recitation of an intended result or functional property of the claimed process must result in a manipulative difference between the claimed process and the cited prior art in order to patentably distinguish the claimed process from the cited prior art. If the prior art process is capable of performing the intended result, or if the functional property naturally flows from the prior art process, then the prior art reads on the intended result or functional property recitation. There is no requirement that the cited prior art expressly teach or suggest the intended result or functional property recitation, but only that the subject matter is, in fact, present in the cited prior art. As outlined above, the manipulative actions positively recited by the claims would have been prima facie obvious over the cited prior art. In particular, Neal and Nadauld combined teach the process steps of initiating a culture with a fragment of distal lung tissue, ad culturing the cells in a 3D air-liquid interface with a culture medium comprising extracellular matrix and an effective concentration of factors for a period of time sufficient to form organoids having bronchiolar and alveolar architecture, without artificial reconstitution, as claimed in claim 1. Therefore, the intended result or functional property of wherein the tissue culture contains endogenous immune cells, mesenchymal cells, and stromal cells would have naturally flowed from performing the process steps taught by Neal and Nadauld combined. Moreover, Neal expressly discloses that the tissue culture recapitulates the cellular architecture and ultrastructure of the tumor sample from which they were derived, and include immune cells, such as tumor infiltrating lymphocytes, and parenchymal and stromal elements, and Nadauld expressly teaches that the tissue culture contains varied cells found in normal mammalian tissues and recapitulates the cellular and tissue ultrastructure including stromal environments. These teachings fairly suggests that cell types natively present in original tissue sample, such as immune cells, mesenchymal cells and stromal cells, are also present in the tissue culture. Accordingly, absent evidence to the contrary, the intended result or functional property recitations are not found to patentably distinguish the claimed invention from the cited prior art.
For these reasons, the process of claim 1 would have been prima facie obvious over Neal and Nadauld combined.
Regarding dependent claims 2-5, the claims further recite the organoids comprise lung epithelial, mesenchymal and immune cells (claim 2); the epithelial cells comprise E-cadherin+ epithelial cells, SFTPC+ AT2 cells, KRT5+ basal cells, SCGB1A1+ club cells, tubulin+ cilia cells, and HT1-56+ AT1 cells (claim 3); the immune cells comprise CD4+ T cells, CD8+ T cells, B cells, and macrophages (claim 4); and the mesenchymal cells are vimentin+ mesenchymal cells (claim 5).
These limitations describe intended results or functional properties that naturally flow from performing the process steps (manipulative actions) positively recited in claim 1. Moreover, Neal expressly recognizes the presence of E-cadherin+ epithelial and vimentin+ stromal cells, B cells, CD4+ T cells, CD8+ T cells, and macrophages. See, par. 15, 20, 29. Therefore, for the same reasons provided above with regards to claim 1, the intended result or functional property recitations of dependent claims 2-5 are not found to patentably distinguish the claimed invention from the cited prior art.
Regarding dependent claim 6, Neal discloses that the tissue is human tissue. See, par. 30. Nadauld teaches that the mammalian tissue is human tissue. See, par. 34.
Regarding dependent claims 7-9, Nadauld teaches that the organoid is infected with an adenovirus. See, e.g., par. 16, 88.
Regarding dependent claim 13, Neal discloses that the cultures can be maintained for up to 28 days or more. See, par. 73. Nadauld discloses that the tissue cultures can be continuously grown for an extended period of time, e.g., for 1 month or more, e.g., for a year or more. See, Abstract, par. 5.
Regarding dependent claims 14-16, Neal discloses the medium for human organoid culture contains EGF and Noggin. The medium further contains A83-01, nicotinamide, and N-acetyl-cysteine, which possess TGF-β inhibitory activity. See, par. 101.
Regarding dependent claim 17, Neal teaches that the tissue cultures are used in screening candidate agents by a process of adding candidate agents to the tissue cultures, and assessing the effect of the candidate agents on the tissue culture. See, par. 36, 79.
Nadauld discloses that the tissue cultures (organoids) find use in many applications, including disease modeling and drug discovery (par. 5). For example, the cells may be exposed to viral or bacterial pathogens to develop a reagent for experiments assessing the anti-viral or anti-bacterial effects of therapeutic agents (par. 80). Diseases that can be modeled in vitro using lung alveolar organoids include viral, bacterial or fungal infection (par. 55). Methods of screening candidate agents for anti-viral or anti-bacterial activity are disclosed, wherein the candidate agent’s ability to inhibit or neutralize a biologically active pathogen is assessed. The organoids are contacted with the agent of interest in the presence of a bacterial, viral or fungal pathogen and the effect of the agent is assessed by monitoring one or more output parameters, such as cell survival / viability, explant growth, etc. See, e.g., par. 84, 103, 111-112.
Regarding dependent claim 21, Neal teaches a step of analyzing the organoid by, e.g., microscopy, histology, staining, etc. See, par. 76, 79.
Nadauld discloses a step of analyzing the organoid by, e.g., microscopy, histology, staining, etc. See, e.g., par. 78, 117.
For these reasons, dependent claims 2-6, 13-17 and 21 also would have been prima facie obvious over Neal and Nadauld combined.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Neal et al. (2018) “Organoid modeling of the tumor immune microenvironment” Cell, 175(7), 1972-1988, which discloses 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).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached at (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
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