DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
This action is responsive to papers filed 10/08/2025.
Claims 17 and 21 have been amended. No claims have been newly canceled and claim 22 has been newly added.
Claims 17-22 are currently pending.
Claim 21 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/20/2025.
Claims 17-20 and 22 have been examined on their merits.
Claim Interpretation
Regarding claim 17, the claim requires administering a composition comprising a population of MSCs and blebbistatin, wherein the population of MSCs and the blebbistatin are incubated together for a period of time prior to the administration to a patient.
The claim does not require a specific length of time for the incubation period and as such once the MSCs and the blebbistatin are brought into contact in a composition prior to administration an incubation period is deemed to be present. This is supported by Applicant’s disclosure which indicates that an incubation period can be about, at least, or more than 0.1 minutes, hours or days prior to administration (page 23 paragraph 85 of Applicant’s Specification). An incubation of about 0.1 minutes is equal to about 6 seconds and deemed to be easily arrived at through ordinary mixing or contact.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 17-20 and 22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lu et al (Diabetes Research and Clinical Practice, 2011-from IDS filed 08/14/2024) in view of Martin-Rendon et al (WO 2011/135380-from IDS filed 08/14/2024), and Schenk et al (WO 2012/062819-from IDS filed 08/14/2024).
Regarding claims 17 and 22, Lu teaches the treatment of disease with stem cell therapy, specifically administering mesenchymal stem cells (MSCs) for the treatment of the symptoms of diabetes (abstract, page 28). Regeneration and healing of damaged tissue is described (healing of ulcers in tissue)(page 33 section 3.5). Lu teaches wherein the disease is a result of peripheral artery disease (PAD) (page 26 Introduction). Lu teaches wherein the population of stem cells comprises multipotent cells, specifically mesenchymal stem cells (MSCs) (Title, abstract, pages 26-28). Intramuscular injection of the MSCs is taught as well as a suitable administration type as well as administration at or in proximity to a site of diseased or damaged tissue (lower limb and ulcer) (page 30 column 1).
Lu does not specifically include blebbistatin in the composition of MSCs administered.
Martin-Rendon teach methods of treating ischemic conditions, such as peripheral artery disease (PAD), by administering therapeutic cells. These therapeutic cells can be combined with supportive cells, such as mesenchymal stem cells (MSCs), for repair of damaged tissue in PAD (page 19 lines 1-14). The MSCs can be expanded on artificial tissue grafts or coating stents for administration to patients (page 19 lines 15-23). Suitable routes of administration include intramuscular (page 20 lines 14-15).
Schenk ‘819 teach a composition that contains mesenchymal stem cells and Blebbistatin (page 19 2nd paragraph) and suggest that this composition can be included as part of a pharmaceutical preparation (page 19 3rd paragraph). The Blebbistatin is taught to provide the benefit of greatly enhancing suspension survival of adherent cells such as MSCs (page 17, 4th paragraph). Schenk also describe how blebbistatin protects MSCs during stressful events such as freezing and thawing (page 5 last paragraph).
One of ordinary skill in the art would have been motivated to include blebbistatin in the method of Lu as part of the administered composition of stem cells because Martin-Rendon and Schenk teach that MSCs can be administered to patients via cell coated substrates such as microcarriers. The combination of the stem cells and the blebbistatin prior to administration provides for an incubation period of time wherein the two ingredients interact (especially if the blebbistatin is used to coat a substrate that the MSCs are then attached to). One of ordinary skill in the art would have been motivated to administer the medicinal composition by intramuscular administration in proximity of damaged tissue because Martin-Rendon indicated that this is a suitable type of administration for this composition combination and Lu also indicated that intramuscular administration in proximity to damaged tissue is suitable and desirable for their method as well. One of ordinary skill in the art would have had a reasonable expectation of success because Schenk ‘819 indicates that a combination of mesenchymal stem cells and Blebbistatin are suitable for use in pharmaceutical preparations (page 19 last paragraph), and Lu and Martin-Rendon are administering mesenchymal stem cells as a pharmaceutical.
Regarding claim 18, Lu teaches wherein the disease is associated with an ankle brachial pressure index (ABI) of less than 0.7 (abstract, page 27 Table 1).
Regarding claim 19, Lu teaches wherein the disease has resulted in critical limb ischemia (Title, abstract, page 26 introduction).
Regarding claim 20, Lu teaches wherein the disease has resulted in skin ulceration (Title, abstract, page 26, page 27 Table 1). Gangrene may be present as well (page 26) and is not excluded from the reference study as long as it is dry and below the ankle (page 27, Table 1).
Therefore, the combined teachings of Lu et al, Martin-Rendon et al, and Schenk ‘819 render obvious Applicant's invention as claimed.
Claims 17-20 and 22 are rejected under pre-AlA 35 U.S.C. 103(a) as being unpatentable over Lu et al (Diabetes Research and Clinical Practice, 2011-from IDS filed 08/14/2024) in view of Chen et al (CN 102940631-published Feb 27, 2013,-from IDS filed 08/14/2024, plus full translation) and Schenk et al (WO 2012/062819-from IDS filed 08/14/2024).
Regarding claims 17 and 22, Lu teaches the treatment of disease with stem cell therapy, specifically administering mesenchymal stem cells (MSCs) for the treatment of the symptoms of diabetes (abstract, page 28). Regeneration and healing of damaged tissue is described (healing of ulcers in tissue)(page 33 section 3.5). Lu teaches wherein the disease is a result of peripheral artery disease (PAD) (page 26 Introduction). Lu teaches wherein the population of stem cells comprises multipotent cells, specifically mesenchymal stem cells (MSCs) (Title, abstract, pages 26-28). Intramuscular injection of the MSCs is taught as well as a suitable administration type as well as administration at or in proximity to a site of diseased or damaged tissue (lower limb and ulcer) (page 30 column 1).
Lu does not specifically include blebbistatin in the composition of MSCs administered.
Chen teaches methods that involve the medicinal application of blebbistatin in promoting stem cell survival (Title, page 1, claims 1-2). The stem cells include mesenchymal stem cells (page 1 claims 1-2). Blebbistatin is also taught as an active ingredient in a pharmaceutical composition for promoting stem cell survival (page 1 claim 2, page 5 para 10) and that it can be administered in combination with other medications for the prevention, management, treatment, or improvement of a condition or one or more symptoms thereof...for example recombinant cells capable of expressing SNX11 (page 4 para 7). Blebbistatin can be administered together with other biologically active agents and the administration is not particularly limited and can be intramuscular (page 4 para 8).
Schenk ‘819 teach a composition that contains mesenchymal stem cells and Blebbistatin (page 19 2nd paragraph) and suggest that this composition can be included as part of a pharmaceutical preparation (page 19 3rd paragraph). The Blebbistatin is taught to provide the benefit of greatly enhancing suspension survival of adherent cells such as MSCs (page 17, 4th paragraph). Blebbistatin can be used for coating the surface of a medical device such as a stent, patch or artificial blood vessel with cells that would otherwise have a low affinity to a surface (page 6), including attachment to microcarrier substrates (page 15). Schenk also describe how blebbistatin protects MSCs during stressful events such as freezing and thawing (page 5 last paragraph).
One of ordinary skill in the art would have been motivated to include blebbistatin in the method of Lu as part of the administered composition of stem cells because Chen teaches that blebbistatin is suitable as an active ingredient in a pharmaceutical composition and can promote stem cell survival and Lu is administering a therapeutic stem cell composition that would benefit from this effect. Enhancing the survival of stem cells allows for the continuation and thus enhancement of their effects and thus enhancement of regeneration of damaged tissue. The combination of the stem cells and the blebbistatin prior to administration provides for an incubation period of time wherein the two ingredients interact (especially if the blebbistatin is used to coat a substrate that the MSCs are then attached to). One of ordinary skill in the art would have been motivated to administer the medicinal composition by intramuscular administration in proximity to damaged tissue because Chen indicated that this is a suitable type of administration for this composition combination and Lu also indicated that intramuscular administration is suitable and desirable for their method as well. One of ordinary skill in the art would have had a reasonable expectation of success because Schenk ‘819 indicates that a combination of mesenchymal stem cells and Blebbistatin are suitable for use in pharmaceutical preparations and Lu is administering mesenchymal stem cells as a pharmaceutical.
Regarding claim 18, Lu teaches wherein the disease is associated with an ankle brachial pressure index (ABI) of less than 0.7 (abstract, page 27 Table 1).
Regarding claim 19, Lu teaches wherein the disease has resulted in critical limb ischemia (Title, abstract, page 26 introduction).
Regarding claim 20, Lu teaches wherein the disease has resulted in skin ulceration (Title, abstract, page 26, page 27 Table 1). Gangrene may be present as well (page 26) and is not excluded from the reference study as long as it is dry and below the ankle (page 27, Table 1).
Therefore, the combined teachings of Lu et al, Chen et al and Schenk ‘819 render obvious Applicant's invention as claimed.
Response to Arguments
Applicant's arguments filed 10/08/2025 have been fully considered but they are not persuasive. Applicant’s arguments have been addressed in so far as they relate to the current rejections.
Applicant argues that the Office did not establish a prima facie case of obviousness because there is no rationale as provided in (C) and (G) as recited in KSR Int’l Co. v. Teleflex according to the MPEP 2143. Applicant asserts that as outlined in (A), (B), (D), (E) and (F) in MPEP 2143 that predictability and/or reasonable expectation of success is critical when establishing a prima facie case of obviousness. Applicant refers to In re Rinehart with regard to the need for a reasonable expectation of success. Applicant refers to MPEP 2143.01 IV with regard to the requirement that modifications be well within the ordinary skill of the art and asserts that the skilled artisan will appreciate that new methods for treating peripheral artery disease (PAD) would be unpredictable with no expectation of success. Applicant also asserts that the Office did not provide a proper reason to combine the cited references and thus failed to establish a prima facie case of obviousness.
This is not found persuasive. The MPEP does not require a prima facie case of obviousness to include every rationale listed from A to G. The obviousness rejections above include both motivation and a reasonable expectation of success as described above.
Applicant argues that Martin-Rendon disclosed that MSCs are used as supportive cells to induce proliferation and/or survival of epithelial progenitor cells (EPCs) or endothelial colony forming cells (ECFCs), which are the cells used to prepare a medicament for treating ischemic conditions (Martin-Rendon page 19, lines 1-14). Applicant asserts that the MSCs disclosed by Martin-Rendon are only used as supportive cells integrated in a graft or stent and not for treating ischemic conditions. Applicant asserts that the Office failed to provide evidence that Martin-Rendon discloses the method as recited in present claim 17. Applicant asserts that there is no disclosure of blebbistatin anywhere in Martin-Rendon to cure the deficiency in Lu.
This is not found persuasive. In response to applicant's arguments against the references individually, 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).
In the current case Martin-Rendon is recited as a secondary reference in the obviousness rejection and teaches methods of treating ischemic conditions, such as peripheral artery disease (PAD), by administering therapeutic cells. These therapeutic cells can be combined with supportive cells, such as mesenchymal stem cells (MSCs), for repair of damaged tissue in PAD (page 19 lines 1-14). Martin-Rendon also disclose the benefit of adhering their cells to a graft for administration to patients as described above.
Applicant argues that the Schenk reference does not disclose the method of claim 17. Applicant asserts that Schenk is limited to a composition for promoting adhesion of stem cells to a substrate to which the stem cells have a low affinity and cannot be applied to stem cell therapy or treating peripheral artery disease.
This is not found persuasive. In response to applicant's arguments against the references individually, 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).
In the current case, Schenk disclose that blebbistatin can be used with MSCs to provide various benefits, including enhancing adherence of cells to a surface for administration as well as for protection of MScs during stressful events and enhancing survival of adherent cells such as MSCs as described above.
Applicant argues that Chen does not teach the method of claim 17 because Chen does not teach administering stem cells and blebbistatin at the same time in combination. Applicant asserts that Chen only discloses administering their blebbistatin compositions to stem cells and does not teach administering blebbistatin with stem cells to treat peripheral artery disease as claimed.
This is not found persuasive. In response to applicant's arguments against the references individually, 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). In the current case, Chen is cited as a secondary reference to provide motivation to the person of ordinary skill in the art to include blebbistatin in the administered composition of Lu because of the benefits of combining MSCs and blebbistatin and the suggestion to include additional agents for the treatment method.
Applicant argues that their claimed method achieves unexpected results and is thus nonobvious. Applicant argues that, even if a POSA was motivated to combined the disclosure of the cited references to arrive at the claimed invention, there would have been no reasonable expectation of success in achieving the same results as disclosed in the instant application. Applicant argues that the claimed invention is based on the beneficial interaction between stem cells and blebbistatin, wherein blebbistatin accelerates and improves stem cells and triggers regeneration of diseased and damaged tissue and reduces complications in healing with combined intramuscular administration.
This is not found persuasive. Both Chen and Schenk teach the combination of stem cells and blebbistatin in a pharmaceutical composition together improves stem cell survival and thus an improvement in therapeutic results would be expected. Schenk even describes how blebbistatin protects MSCs during stressful events such as freezing and thawing (page 5 last paragraph) which would suggest that the cells administered with the protective effects of blebbistatin are in better condition than those that are only pre-treated.
Applicant argues that Table 5 of their specification shows that a combined administration of MSCs and blebbistatin resulted in significantly more pronounced therapeutic effect than cells only pretreated with blebbistatin. Applicant asserts that none of the cited references disclosed the advantageous therapeutic effects of the combination of MSCs and Blebbistatin and thus could not have been expected from any of the cited references.
This is not found persuasive. Both Chen and Schenk teach the combination of stem cells and blebbistatin in a pharmaceutical composition together improves stem cell survival and thus an improvement in therapeutic results would be expected. Schenk even describes how blebbistatin protects MSCs during stressful events such as freezing and thawing (page 5 last paragraph) which would suggest that the cells administered with the protective effects of blebbistatin are in better condition than those that are only pre-treated.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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