DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 11 August 2025 have been entered. Claims 12-22 were previously 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 12-22 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
The objection to amended claim 12 for reciting “intracorpareal” is withdrawn in view of the amendment to claim 1 which now recite “intracorporeal”.
Claim Rejections - 35 USC § 112(b)
The rejection of amended claims 12-22 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:
Independent claim 12 reciting, "the active ingredient" in line 3;
Claim 13 reciting, "the extracorporeal endothelium" in line 2 and “wherein the extracorporeal endothelium is comprised in an extracorporeal tissue or organ, which is located outside of the body of a patient and artificially perfusing the extracorporeal tissue or organ separate from the blood circulation of the patient”; BUT new issue…
Claim 16 reciting, "the extracorporeal tissue or organ" in lines 1-2;
Independent claim 17 reciting, “Method of treatment of epithelium by the treatment of epithelium, comprising a first composition containing 17β-estradiol as the active ingredient, and a second composition comprising a suspension of cells, wherein the second composition is for contacting the epithelium at a time after the contact with the first composition”, the active ingredient" in lines 2-3, and “the contact with the first composition” in lines 4-5;
Claim 19 reciting, “wherein the epithelium is located in or at a patient” and that the patient is “undergoing the treatment”;
Claim 20 reciting, “wherein the epithelium is perfused”, "the patient" in line 2, and that the patient is “undergoing the treatment”;
Claim 22 reciting, "the tissue or organ" in line 5 and again in line 6;
is withdrawn over amended claims 12 and 14-16 and maintained in modified form over amended claims 13 and 17-22 in view of Applicant’s amendments to the claims such that:
Independent claim 12 now recites, "an active ingredient" in line 3;
Claim 13 no longer reciting, "the extracorporeal endothelium" nor “wherein the extracorporeal endothelium is comprised in an extracorporeal tissue or organ, which is located outside of the body of a patient and artificially perfusing the extracorporeal tissue or organ separate from the blood circulation of the patient”;
Claim 16 still reciting, "the extracorporeal tissue or organ", but now depending from amended claim 13;
Independent claim 17 now reciting, “A method of treatment of epithelium comprising contacting the epithelium with a first composition containing 17β-estradiol as the active ingredient, and subsequently perfusing the epithelium with a second composition comprising a suspension of cells”, such that claim 17 now recites active method steps; and now longer reciting “the contact with the first composition” in lines 4-5;
Claim 19 no longer reciting, “wherein the epithelium is located in or at a patient”;
Claim 20 no longer reciting, “wherein the epithelium is perfused” nor "the patient";
Claim 22 reciting, "a tissue or organ";
Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Amended independent claim 17 still recites “the active ingredient” in line 3, and so has not overcome the rejection of record in that “the active ingredient” still lacks antecedent basis. As such, the metes and bounds of the claim cannot be determined.
Amended claims 19 and 20 each still recite “a patient undergoing the treatment”, which is still indefinite because claim 17, upon which claim 19 depends, recites a method of treatment of epithelium, not a method of treating a patient. Therefore, there is insufficient antecedent basis for this limitation in the claim. As such, the metes and bounds of the claims cannot be determined.
Amended claim 13 newly recites “comprising artificially perfusing extracorporeal tissue or organ separate from blood circulation of a patient to obtain the extracorporeal epithelium from the extracorporeal tissue or organ”, which has two issues of indefiniteness. Firstly, “comprising artificially perfusing” is indefinite because it is unclear whether the recited step of “artificially perfusing” is an additional method step or whether it is meant to be the perfusing step recited in claim 12. Secondly, “perfusing extracorporeal tissue or organ… to obtain the extracorporeal epithelium from the extracorporeal tissue or organ” is indefinite because it is unclear how perfusing a tissue or organ results in obtaining an epithelium from the tissue or organ. As such, the metes and bounds of the claim cannot be determined.
Amended claim 19 newly recites, “wherein the contacting and perfusing each comprise contacting the epithelium of patient”, which is indefinite because although the contacting step of independent claim 17, upon which claim 19 depends, recites “contacting the epithelium with a first composition”, it is unclear what the perfusing is meant to be contacting the epithelium with. For example, it is unclear whether the “contacting” being done in the perfusing step is the perfusing the epithelium with a second composition or whether the “contacting” comprised in the perfusing step is an additional contacting, wherein the epithelium of a patient is additionally contacted with any unlimited composition. As such, the metes and bounds of the claim cannot be determined.
Amended claims 19 also newly recites, “contacting the epithelium of a patient undergoing the treatment” which is indefinite because it is unclear whether “the epithelium” is meant to refer to the epithelium recited in independent claim 17, upon which claim 19 depends, or whether “the epithelium of a patient” is meant to be any epithelium associated with a patient. As such, the metes and bounds of the claim cannot be determined.
Amended claim 22 newly recites, “wherein the contacting and perfusing comprise perfusing, flushing, or contacting with an aerosol a tissue or organ”, which is indefinite because it is unclear whether the “contacting and perfusing” are meant to collectively comprise “perfusing, flushing, or contacting with an aerosol” or whether each step of “contacting” and “perfusing” is meant to comprise “perfusing, flushing, or contacting with an aerosol”. If the latter, then it is further unclear how a step of “perfusing” can comprise “flushing, or contacting with an aerosol”. As such, the metes and bounds of the claim cannot be determined.
Applicant asserts that Examiner’s observations were carefully considered and addressed via responsive amendments. However, this is not agreed. Although Applicant has addressed most of the issues of indefiniteness identified in the prior action, as described above, a few issues remain. Additionally, new issues of indefiniteness were introduced by way of amendment. Therefore, Applicant’s arguments do not overcome a finding of indefiniteness for claims 13 and 17-22.
Claim Rejections - 35 USC § 101
The rejection of amended claims 17-22 under 35 U.S.C. 101 as being directed to non-statutory subject matter, is withdrawn in view of Applicant’s amendments to the claims such that claim 17 now recites active method steps.
Claim Rejections - 35 USC § 103
The rejection of amended 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 maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the claims for clarity to address several issues of indefiniteness identified in the prior action. However, Applicant’s amendments have not substantially altered the scope of the claims as written, and as such have not introduced any new limitations which overcome the rejection of record.
To the extent that the amendment to claim 18 has removed the limitation that the epithelium is defective epithelium while newly reciting that the epithelium comprises defective endothelium, note that although Mordant was cited for teaching the treatment of damaged/ injured pig lung [abstract, column 9 ¶ 2, column 10 ¶ 2, column 11 ¶ 1-2, column 13 ¶ 1], which comprise both epithelial and endothelial tissues.
Applicant argues that:
Mordant, Wetsel, and Pearson provide no reason or rationale to contact the lung with a composition containing 17β-estradiol (E2);
Pearson’s teachings only apply to impairment of retinal OLM integrity and only indicate that genetic manipulation to suppress the expression of CRB1 protein or ZO-1 protein can be used to improve integration of cells into a retina;
Groten has no teachings for integration of cells and that the teachings of E2 treatment transiently redistributing adherens junction proteins only refers to VE-cadherin, β-catenin, and α-catenin without referring to the CRB1 protein or ZO-1 protein taught by Pearson, such that the combination of Pearson and Groten would not be obvious.
However, this is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding argument 1), note that Mordant and Wetsel were not relied on for teaching E2 administration prior to cellular transplant. Additionally, Pearson was cited for teaching that disruptions to adherens junctions promote the integration of transplanted cells. As such, none of Mordant, Wetsel, nor Pearson were specifically relied on to specifically teach E2 treatment.
Regarding Applicant’s argument 2), although Pearson is specifically reporting on studies focused on manipulations of CRB1 and ZO-1, including transient siRNA knockdown, the effect is to disrupt the integrity of the adherens junctions, and as such, the increased transplanted cell integration observed was due to the disruption of the adherens junctions [abstract, column 3 ¶ 2, column 8 ¶ 2, Figure 1]. Pearson also teaches that the adherens junctions are transmembrane cadherin-catenin complexes (including β-catenin, ZO-1, and N-cadherin) that mediate cell-cell adhesion, which interact with a cytoplasmic plaque comprising adaptor proteins (including CRB1) [column 3 ¶ 2, Figure 1]. Pearson additionally teaches that inducing a transient disruption of the physical barrier formed by the adherens junctions connecting the cells, when combined with cell transplantation, led to significant improvements in integration [column 16 ¶ 1].
Pearson further teaches that either pharmacological interference or genetic disruption of a number of components of the adherens junction and/or the supporting scaffold leads to significant impairment in OLM integrity [column 3 ¶ 2]. Therefore, Pearson is teaching that disruption in any of the components of the adherens junction or supporting scaffold will lead to adherens junctions impairment, and that either pharmacological interference with the junctions or genetic disruption of the junctions will lead to such impairments, even when the interference is transient. Accordingly, Pearson is teaching the motivation to disrupt adherens junctions to facilitate the integration of transplanted cells.
Regarding argument 3), note that Groten was not relied on for teaching the integration of transplanted cells. Groten was cited for teaching that 17β-estradiol (E2) regulates migration, proliferation, and wound healing and also increases 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]. Therefore, Groten teaches that E2 causes adherens junction impairment. Additionally, Groten teaches that E2 mediates disruption of endothelial adherens junctions through increased tyrosine phosphorylation of β-catenin and dissociation of α-catenin from the adherens junction complex [page 9 ¶ 3- page 10 ¶ 1].
As such, given the teachings of Pearson that disruption of adherens junctions promotes the integration of transplanted cells, and the teachings of Groten that E2 mediates the disruption of adherens junctions, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to treat an epithelial/endothelial tissue with E2 prior to perfusing a suspension of cells to disrupt the adherens junctions of the tissue and promote integration of the perfused/transplanted cells. An ordinarily skilled artisan at the time of filing the instant application would additionally have a reasonable expectation of success in so doing given the teachings of Groten that E2 disrupts adherens junctions and Pearson that disruption of adherens junction overcomes a physical barrier to promote cell integration. Accordingly, 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 incorporate a step of contacting the epithelium with 17β-estradiol prior to administration of a suspension of cells for transplant to improve the integration of the transplanted cells within the epithelial tissue with a reasonable expectation of success.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Mordant, Wetsel, Pearson, and Groten under 35 USC 103, and the rejection of record is maintained.
Conclusion
No claim is allowed.
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 Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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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