DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 18 May 2026 have been entered. Claims 12-22 were previously pending in the application. Claim 19 has been cancelled, and no new claims have been added by Applicant. Claims 12-18 and 20-22 are currently pending in the application. Claims 12 and 17 are independent claims.
The election of Group II, drawn to a process for treatment of an extracorporeal epithelium or of an intracorporeal epithelium and a method of treatment of epithelium, remains in effect in the instant application.
The following election of species remains in effect in the instant application:
Cells: c. progenitors of epithelial cells,
Epithelial tissue/organ: epithelial/endothelial layer of a lung.
Claims 12-18 and 20-22 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2020/065495, filed 04 June 2020, which claims priority to European Patent Office Application No. EPO19178122.8, filed 04 June 2019. Filing of a certified copy of the EPO19178122.8, filed 30 November 2021, is acknowledged.
Thus, the earliest possible priority for the instant application is 04 June 2019.
Claim Objections
Amended claims 13 and 20 are newly objected to because of the following informalities: amended claims 13 and 20 each newly recite “conducing” in lines 4 and 3, respectively, which appear to be typographical misspellings of “conducting”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and previously presented claims 13 and 17-22 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn in view of Applicant’s amendments to the claims addressing the identified issues of indefiniteness.
Claim Rejections - 35 USC § 103
The rejection of amended and cancelled claims 12-22 under 35 U.S.C. 103 as being unpatentable over Mordant et al. [2016, The Journal of Heart and Lung Transplantation, 35(10), 1245-1254]; in view of Wetsel et al. [2011, Annu. Rev. Med., 62, 95-105, published online 17 November 2010]; Pearson et al. [2010, Cell Transplantation, 19, 487-503]; and Groten et al. [2005, The FASEB Journal, 19(10), 1368-1370, published online 31 May 2005, IDS], is withdrawn in view of Applicant’s claims which now recite “wherein the concentration of 17β-estradiol in the medium is at least 1 µM” in lines 3-4 of each of claims 1 and 17.
**The following new rejection is necessitated by Applicant’s amendments to the claims.
Amended and previously presented claims 12-18 and 20-22 are newly rejected under 35 U.S.C. 103 as being unpatentable over Mordant et al. [2016, The Journal of Heart and Lung Transplantation, 35(10), 1245-1254]; in view of Wetsel et al. [2011, Annu. Rev. Med., 62, 95-105, published online 17 November 2010]; Pearson et al. [2010, Cell Transplantation, 19, 487-503]; Groten et al. [2005, The FASEB Journal, 19(10), 1368-1370, published online 31 May 2005, IDS]; Hamidi et al. [2011, Endocrinology, 152(12), 4729-4737]; and Nelson et al. [2014, World Journal of Experimental Medicine, 4(2), 7-15].
Mordant teaches a process for treatment of an extracorporeal epithelium (e.g., lung epithelium) comprised in an extracorporeal tissue or organ (e.g., donor lung) which is located outside of the body of a patient, comprising contacting (e.g., ex vivo lung perfusion (EVLP)) the epithelium with a perfusion fluid/third composition that is free from E2 and free from added cells, and after contacting the epithelium with the first composition, contacting (e.g., intrabronchially (IB) IB or intravascularly (IV) the epithelium with a second composition comprising a suspension of cells (e.g., mesenchymal stem cells (MSCs)) [abstract, column 3 ¶ 3-4]. Mordant further teaches wherein intravascular administration of MSCs was associated with significant and sustained retention of MSCs in lung parenchyma [abstract], wherein the perfusion of MSCs comprises separating the epithelium from blood circulation of a patient (i.e., lung blocks were retrieved from donor pigs) and then conducting the perfusing of the lung (i.e., Ex vivo lung perfusion (EVLP was started), which necessarily and inherently requires connecting the epithelium to an artificial medium circulation system to perform the perfusion [col 3 ¶ 2-4]. Further, Mordant teaches an “EVLP circuit” [col 11 ¶ 2].
By teaching ex vivo lung perfusion, Mordant necessarily teaches that the contacting/ perfusing is separate from the blood circulation of the patient. Mordant further teaches that the contacting with the first composition is carried out for at least 5 minutes (e.g., 1 hour) prior to the subsequent contacting of the epithelium with the second composition for at least 15 minutes (e.g., cells were administered to both lungs during the second hour of EVLP over the course of at least 15-30 minutes and left for the duration of the experiment- at least up to 3, ,12, or 18 hours) [column 3 ¶ 3-4, 5, column 5 ¶ 1, 3, Figure 1a]. Mordant additionally teaches that the ex vivo EVLP and IV administration of MSCs was carried out with damaged/injured pig lungs which had epithelial apoptosis/defective epithelium [column 2 ¶ 4, column 9 ¶ 2, column 10 ¶ 2, column 11 ¶ 2, Figure 6c].
Mordant does not teach that the suspension of cells is a suspension of progenitors of epithelial cells. Mordant additionally does not teach that the first composition comprises at least 1 µM 17β-estradiol (E2) as an active ingredient in a medium which is contacted with the epithelium for a maximum of 3 hours. However, Wetsel, Pearson, Groten, and Hamidi cure these deficiencies.
Wetsel teaches the therapeutic potential of lung epithelial progenitor cells derived from embryonic and induced pluripotent stem cells (IPSC) in lung regenerative medicine [title, abstract]. Wetsel teaches that patient-specific iPSC could be obtained, thereby avoiding the immune rejection problems that might occur if heterologous sources of stem cells were employed, and additionally offer the possibility of gene-corrected, patient-specific lung progenitor cells from individuals with genetic disease affecting the lungs [column 6 ¶ 1]. Wetsel additionally teaches that intrapulmonary administration of bone marrow-derived MSCs attenuates inflammation and lung injury [column 14 ¶ 2]. Wetsel further teaches that because of their robust pluripotent nature, hES and iPS cells may exhibit more therapeutic potential for gene delivery and the repair and regeneration of injured lung epithelium than adult bone marrow-derived stem cells (e.g., MSCs), but that the direct administration of hES or iPS cells could pose a risk of teratoma formation, especially to patients who are immune-compromised [column 14 ¶ 3]. Therefore, Wetsel teaches, clinical applications of human pluripotent cells in pulmonary medicine are likely to be performed by using hESC- or iPSC-derived lunch progenitor cells in transplantation studies. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to utilize epithelial progenitor cells rather than MSCs in a cell transplantation method for the treatment of damaged/injured/defective lung epithelium or endothelium to capitalize on the greater therapeutic potential of hESC/iPSC cells in repair and regeneration while reducing the risk of teratoma formation.
Pearson teaches that adherens junctions are transmembrane cadherin-catenin complexes that mediate cell-cell adhesion and impede transplanted cells from migrating into the recipient tissue [abstract, column 3 ¶ 2]. Pearson also teaches that disruption of adherens junctions increases transplantation efficiency by increasing integration of transplanted cells in both wild-type mice and mice with degenerated/ damaged tissues [abstract, column 2 ¶ 1, column 3 ¶ 3]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to disrupt the adherens junctions of a recipient tissue which is being targeted for cell transplantation to increase the permeability of the target tissue and thereby increase integration of the exogenous cells into the tissue.
Groten teaches that 17β-estradiol (E2) regulates migration, proliferation, and wound healing and also increase endothelial monolayer permeability by transiently disrupting adherens junctions by disconnecting the adherens junction complex from the cytoskeleton in endothelial cells [title, abstract, page 1 ¶ 1, page 3 ¶ 1, page 8 ¶ 4- page 9 ¶ 1]. Groten also teaches the treatment of endothelial cells with E2 for 30 or 60 minutes is sufficient to enhance monolayer permeability to FITC-labeled dextran, and that no additional increase was noted at two hours or beyond [page 3 ¶ 3, page 5 ¶ 4, Figure 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to treat a recipient tissue comprising adherens junctions (e.g., endothelium or epithelium) with E2 for 30 minutes to 2 hours to permeabilize the recipient tissue prior to administration of exogenous cells for transplantation.
Hamidi teaches that treatment of an epithelium (i.e., a lung comprising both epithelial and endothelial tissue) with 1 µM 17β-estradiol (E2) protects the epithelium/lung against acute injury, including protection against oxidative injury, excitotoxic injury, and anoxia-induced injury [abstract, pg 4731 col 1 ¶ 6- col 2 ¶ 2, pg 4732 col 1 ¶ 3- pg 4733 col 1 ¶ 1, Figure 3, 4, 5]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to expose an epithelium to 17β-estradiol at a dose of about 1 µM to protect the epithelium from a variety of injuries.
Regarding amended claim 22, Mordant, Wetsel, Pearson, Groten, and Hamidi do not explicitly teach wherein the perfusing comprising contacting the epithelium with an aerosol.
Nelson teaches that pulmonary delivery of aerosolized drugs has been modeled using an EVLP system by many groups, such that administration of aerosolized drug resulted in a significantly higher uptake of drug in the respiratory epithelium compared to administration of drug along using an EVLP model [pg 9 col 2 ¶ 5]. Therefore, Nelson teaches the motivation for an ordinarily skilled artisan at the time of filing to include contacting the epithelium with an aerosol for effective administration of a drug during EVLP.
Given the teachings of Wetsel of the therapeutic potential of lung epithelial progenitor cells derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (IPSC) in lung regenerative medicine; the motivation taught by Wetsel to utilize epithelial progenitor cells rather than mesenchymal stem cells (MSCs) in a cell transplantation method for the treatment of damaged/injured/defective lung epithelium or endothelium to capitalize on the greater therapeutic potential of hESCs/iPSCs in repair and regeneration while reducing the risk of teratoma formation; the motivation taught by Pearson to disrupt the adherens junctions of a recipient tissue which is being targeted for cell transplantation to increase the permeability of the target tissue and thereby increase integration of the exogenous cells into the tissue; the motivation taught by Groten to treat a recipient tissue comprising adherens junctions (e.g., endothelium or epithelium) with E2 for 30 minutes to 2 hours to permeabilize the recipient tissue; and the motivation taught by Hamidi to expose an epithelium to 17β-estradiol at a dose of about 1 µM to protect the epithelium from a variety of injuries; and the motivation taught by Nelson to include contacting the epithelium with an aerosol for effective administration of a drug during EVLP; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method of Mordant to include a step of contacting the recipient donor lung tissue/organ with a first composition comprising 1 µM 17β-estradiol (E2) for 30 minutes to 2 hours to permeabilize and protect the tissue prior to contacting the donor lung tissue/organ with a third perfusion composition free of E2 and free of cells, and to subsequently contact the lung tissue/organ with a second composition comprising a suspension of epithelial progenitor cells with a reasonable expectation of success.
Insofar as applicant’s arguments apply to this new grounds of rejection, Applicant argues that:
the feature of “contacting the epithelium with a first composition containing 17β-estradiol as an active ingredient in a medium, wherein the concentration of 17β-estradiol in the medium is at least 1 µM” is completely missing in the art;
in Groten’s experiments, treatments used 10 nM 17 α-estradiol, and so the sweeping conclusion of obviousness in the paragraph bridging pages 9 and 10 of the final office action is not a rationale supported by evidence such that there is no evidence of using an artificially high level of “17β-estradiol as an active ingredient in a medium, wherein the concentration of 17β-estradiol in the medium is at least 1 µM” as required by claims 12 and 17; and
the references together as a whole fail to indicate evidence of a rationale that demonstrates obviousness in that nothing in Mordant, Wesel, or Pearson provides evidence of a rationale to use an artificially high level of 17β-estradiol as an active ingredient in a medium, wherein the concentration of 17β-estradiol in the medium is at least 1 µM.
However, this is not agreed.
Regarding Applicant’s arguments 1 and 3), note that Hamidi was cited for teaching the use of 1 µM 17β-estradiol to protect epithelium from various acute injuries, thereby teaching the motivation to expose an epithelium to 17β-estradiol at a dose of about 1 µM to protect the epithelium from a variety of injuries. Additionally, Groten was cited for teaching the motivation treat a recipient tissue comprising adherens junctions (e.g., endothelium or epithelium) with E2 for 30 minutes to 2 hours to permeabilize the recipient tissue prior to administration of exogenous cells for transplantation.
Regarding Applicant’s argument 2), although Groten used 17 α-estradiol in a comparative experiment to determine the specificity of 17β-estradiol, the conclusions provided in the final paragraph relate to teachings presented by Groten specifically referencing and/or using 17β-estradiol (E2), specifically the teachings of Groten that E2 mediates the disruption of adherens junctions [abstract, pg 2 ¶ 4-pg 3 ¶ 1, pg 8 ¶ 2, pg 9 ¶ 2, pg 10 ¶ 1, pg 11 ¶ 1, Figure 1, 2, 3, 4, 7]. Further, Groten teaches testing whether the effect of E2 on α-catenin/VE-cadherin colocalization was specific for 17β-estradiol and determining that progesterone and the biologically active E2 isomer 17 α-estradiol did not effect colocalization of the two proteins, thereby showing that in fact the E2-induced effect was E2-specific.
Therefore, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Mordant, Wetsel, Pearson, Groten, Hamidi, and Nelson.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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