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 August 31, 2026.
Notice of Non-responsive Amendment
Applicant’s reply filed on 08/31/2026 is not fully responsive to the prior Office Action because of the following omission(s) or matter(s):
37 CFR 1.121(c)(4) states:
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of "canceled" or "not entered."
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as "canceled" will constitute an instruction to cancel the claim.
Applicant’s amendment to the claims does not comply with one or more of these requirements. In this case, claims 14-16 are canceled by the amendment, but the amendment also presents the previous claim text with strike-through markings. As required by 37 CFR 1.121(c)(4), no claim text should be presented for any canceled claim. While entry of the amendment has been accepted in this instance, Applicant is respectfully reminded to comply with the requirements of 37 CFR 1.121(c) when making amendments to the claims.
Claim Amendments
Applicant’s amendment to the claims filed 08/31/2026 is acknowledged.
Claims 14-16, 20 and 22 have been cancelled.
Claim 23 is newly added.
Claims 1, 6, 9, 11-12, 17 and 21 are amended.
Claims 1-13, 17-19, 21 and 23 are pending and under examination.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 04/29/2026 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Applicant’s arguments filed 08/31/2026 have been carefully considered, but are found to be moot in view of the new grounds of rejection set forth in this action.
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.
Claim Objections
Claims 11 and 21 are objected to because of the following informalities:
In claim 11, line 3, the phrase “pneumoniae; Chlamydia” should be “pneumoniae, Chlamydia” instead.
In claim 21, line 2, the phrase “imaging; quantitative” should be “imaging, quantitative” instead.
Appropriate action is required.
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 1-11, 13, 17-19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0302491 A1 to Nadauld et al.; in view of US 2017/0275592 A1 to Sachs et al.
This rejection is newly applied, necessitated by amendment.
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. "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). See also, MPEP 2144.01. In this case, alveoli and distal bronchioles constitute the parenchyma of lung tissue and is located within the peripheral of the lung. Accordingly, since the lung tissue in Nadauld contains both bronchiolar and alveolar architecture, Nadauld is found to teach or fairly suggest a step of initiating a culture with a fragment of peripheral lung tissue containing alveoli and distal bronchioles, as instantly claimed.
The gel substrate is a semi-solid extracellular matrix containing collagen. 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 teach or fairly suggest 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 peripheral lung tissue containing alveoli and distal bronchioles; and
culturing the cells in a 3D air-liquid interface with a culture medium containing an extracellular matrix comprising collagen 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.
Nadauld does not teach a culture medium containing an effective concentration of EGF, Noggin, a TGF-β inhibitor, a ROCK inhibitor and a GSK-3 inhibitor, as instantly claimed.
Sachs is relevant prior art for teaching improved culture methods for expanding epithelial stem cells and obtaining organoids, and culture media therefor. See, Abstract. The organoids include lung organoids and culture media therefor. See, e.g., par. 21-23.
In the working examples (Example 5), organoids derived from human lung tissue were cultured in a medium comprising the receptor tyrosine kinase ligand EGF, the Wnt agonist Rspondin (Rspo), the BMP inhibitor Noggin, the TGFβ inhibitor A83-01 and the ROCK inhibitor Y-27632. See, par. 640. See also, par. 209 and 217 of the specification, disclosing an organoid culture media comprising one or more receptor tyrosine kinase ligands (e.g., EGF), a BMP inhibitor (e.g., Noggin), a TGFβ inhibitor (e.g., A83-01), a ROCK inhibitor (e.g., Y-27632) and one or more Wnt agonists. The Wnt agonists inhibit GSK-3. See, par. 118 and 127.
BMP inhibitors, such as Noggin, promote expression of Lgr5, resulting in more proliferative organoids (par. 109-110, 115); the Wnt agonists, such as Rspondin or CHIR99021, activate Lgr5 and inhibit GSK-3 (par. 117-118, 127); the receptor tyrosine kinase ligand EGF is a potent mitogenic factor and maybe beneficial for growth of organoids (par. 137, 140-141); the TGFβ inhibitor, such as A83-01, increases organoid formation efficiency (par. 149, 154); and the ROCK inhibitors, such as Y-27632, prevent anoikis, which is a form of programmed cell death (par. 159).
The culture medium may be further diffused into an extracellular matrix (ECM) composed of collagen, which provides a 3D scaffold for tissue-like structures. See, par. 306, 308 and 523.
For these reasons, Sachs is found to teach or fairly suggest a culture media for lung organoids comprising collagen and an effective concentration of EGF, Noggin, a TGFβ inhibitor, a ROCK inhibitor and a GSK-3 inhibitor, as instantly claimed.
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 using a culture media comprising collagen and an effective concentration of EGF, Noggin, a TGFβ inhibitor, a ROCK inhibitor and a GSK-3 inhibitor, as taught by Sachs, with a reasonable expectation of success because the culture media of Sachs is suitable for lung organoid culture, providing an effective amount of factors beneficial for organoid formation and growth.
Claim 1 further recites that the tissue culture contains endogenous immune cells, mesenchymal cells and stromal cells, and the bronchioles extend into alveoli. Nadauld discloses that the tissue culture contains varied cells found in normal mammalian tissues and recapitulates the cellular and tissue ultrastructure, including stromal environments. Further, with respect to lung organoid culture specifically, Nadauld describes the organoids as having bronchiolar and alveolar architecture. However, Nadauld does not expressly identify endogenous immune cells and mesenchymal cells in the tissue culture, nor are the bronchioles expressly described as extending into alveoli, as instantly claimed.
"[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 limitations wherein the tissue culture contains endogenous immune cells, mesenchymal cells and stromal cells and wherein the bronchioles extend into alveoli describe 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 prior art. In particular, Nadauld teaches a process of 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 having bronchiolar and alveolar architecture, without artificial reconstitution, and Sachs discloses a lung organoid culture media comprising collagen and an effective amount of EGF, Noggin, TGFβ inhibitor, a ROCK inhibitor and a GSK-3 inhibitor, as instantly claimed. Therefore, the intended result or functional property of wherein the tissue culture contains endogenous immune cells, mesenchymal cells and stromal cells and wherein the bronchioles extend into alveoli would have naturally flowed from performing the process steps taught by Nadauld and Sachs combined. 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. In addition, in a working example of lung organoid culture, Nadauld describes the organoids as having bronchiolar and alveolar architecture, which fairly suggests successful recapitulation of the native distal lung structure, i.e., where bronchioles extend into alveoli. 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 Nadauld and Sachs 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. 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 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, Sachs discloses use of the lung organoids as ex vivo infection models. The lung organoids are cultured with a pathogen, such as Mycobacterium tuberculosis or Streptococcus pneumoniae. See, e.g., par. 541-542.
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 infecting the lung organoids with a respiratory pathogen, such as Mycobacterium tuberculosis or Streptococcus pneumoniae, as taught by Sachs, with a reasonable expectation of success because Nadauld teaches the lung alveolar organoids are useful to model bacterial infection, and infecting the organoids respiratory pathogens, such as Mycobacterium tuberculosis or Streptococcus pneumoniae, would have provided a model to study and evaluate respiratory infection by the pathogen.
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 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, Sachs discloses use of the lung organoids in vaccine development and/or production. Lung organoids are cultured with a pathogen, and the vaccine is used to, for example, prevent and/or treat tuberculosis, pneumonia or respiratory syncytial virus infection. See, e.g., par. 486, 541-542.
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 contacting the tissue culture with a vaccine, as taught by Sachs, 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 evaluating the pharmacological properties of the vaccine in an ex vivo environment.
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 2-11, 13, 17-19 and 21 would have also been prima facie obvious over the prior art.
Claims 12 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Nadauld and Sachs, as applied to the claims 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.
This rejection is newly applied, necessitated by amendment.
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.
Claim 12 further recites that the organoids are removed from the culture medium comprising collagen by treatment with collagenase. Co removed the organoids from the culture medium comprising extracellular matrix by dislodging the organoids with a sterile spatula (i.e., mechanical dissociation), and EDTA was added to maintain organoid integrity during removal by disrupting divalent cation-dependent polymerization of the ECM protein laminin. See, pg. 2510-2511, joining paragraph, and see page e3, “Enteroid suspension culture,” of the detailed Methods. Co does not teach collagenase treatment in removing the organoids from the culture medium.
However, prior to the effective filing date of the instantly claimed invention, collagenase was a known enzyme used to in cell culture to isolate adherent cells by degrading collagen, i.e., a process of enzymatic dissociation. Official Notice taken, if necessary.
Accordingly, one of ordinary skill in the art would have recognized that (i) mechanical dissociation or (ii) enzymatic dissociation were alternative means of dissociating and isolating cells from a culture medium comprising extracellular matrix, and the enzyme collagenase, in particular, may be used when the extracellular matrix comprises collagen. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to substitute mechanical dissociation, as found in Co, with collagenase treatment, as previously known in the art with a reasonable expectation of success because collagenase treatment would degrade the collagen used in the cell culture of Nadauld and Sachs combined, enabling isolation of the organoids form the culture medium, and the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
For these reasons, dependent claim 12 would have been prima facie obvious over the prior art. Claim 23 is included in the basis of this rejection because the limitations of claim 23 are found in the other claims and have been addressed above.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Salahudeen et al. (25 Nov 2020) “Progenitor identification and SARS-CoV-2 infection in human distal lung organoids” Nature, Vol. 588, pp. 670-675, discloses a method for the ex vivo culture distal lung organoids containing terminal bronchioles and alveoli with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection with SARS-CoV-2. See, Abstract.
The cell culture was initiated with a fragment of peripheral lung tissue within 1 cm of the visceral pleura, and the organoids were cultured in a medium comprising extracellular matrix (ECM) and an effective concentration of Noggin, EGF and TGFβ inhibitor A83-01. See, detailed Methods, first page, left column.
Apical-out polarity was achieved by a process comprising dislodging embedded lung organoids from ECM droplets through gentle pipetting (i.e., mechanical dissociation), and placing the organoids in suspension culture. See, detailed Methods, third page, left column.
US 2018/0119107 A1 to Neal et al. discloses methods for in vitro culture systems of human solid tumors as 3-dimernesional (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.
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).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
