DETAILED ACTION
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 .
This action is responsive to papers filed 01/31/2025.
Claims 1-17 are currently pending and have been examined on their merits.
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-11 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Blitzer et al (Cytotherapy, 2022) in view of Chen et al (Stem Cells International 2018).
Regarding claims 1, 3, 5, 8, 15-17, Blitzer disclose a method for treating xerostomia after radiation therapy and/or chemotherapy by administering marrow derived autologous stromal cells that have been stimulated by IFN-gamma (abstract and page 4). Blitzer disclose that cryopreserving the BM-MSCs allows the benefit of a ready supply of cells for multiple injections and that stimulating BM-MSCs with IFN-gamma prior to cryopreservation has been shown to prevent immune dysfunctionality due to cryopreservation (page 3 last paragraph). Blitzer disclose wherein the subjects are human (abstract, page 3 last paragraph, page 4 first paragraph).
Blitzer do not specifically include stimulating the MSCs with TNF-alpha as well as IFN-gamma.
Chen disclose that proinflammatory cytokines such as TNF-alpha have been shown to enhance the effect of IFN-gamma on MSC priming through the production of IDO or PGE2 (page 3 column 2, last paragraph). Chen disclose that transplantation of MSCs derived from the salivary gland restore salivary gland function in radiation-damaged rat salivary glands (page 4 column 1). Chen also disclose that treatment with BMSCs prevents decline in the salivary flow rate and lymphocytic infiltrations in the salivary glands of NOD mice (model for human research)(page 4, column 2).
One of ordinary skill in the art would have been motivated to include stimulation of the MSCs with both IFN-gamma and TNF-alpha prior to cryopreservation of the MSCs in the method of Blitzer because Chen teach and suggest that TNF-alpha has been shown to enhance the effect of IFN-gamma on MSC priming through the production of IDO and PGE2. Blitzer also disclose that cryopreserving the BM-MSCs allows the benefit of a ready supply of cells for multiple injections and that stimulating BM-MSCs with IFN-gamma prior to cryopreservation has been shown to prevent immune dysfunctionality due to cryopreservation (page 3 last paragraph). One of ordinary skill in the art would have had a reasonable expectation of success because both Chen and Blitzer teach the treatment of xerostomia with the administration of primed MSCs.
Regarding claim 2, while Blitzer and Chen are silent with regard to the MSCs having an increased secretion of R-spondin 3 after being treated with a combination of IFN-gamma and TNF-alpha, this effect is deemed to be inherent to the combination. Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).
Regarding claim 4, Blitzer also disclose that cryopreserving the BM-MSCs allows the benefit of a ready supply of cells for multiple injections and that stimulating BM-MSCs with IFN-gamma prior to cryopreservation has been shown to prevent immune dysfunctionality due to cryopreservation (page 3 last paragraph). Chen disclose that proinflammatory cytokines such as TNF-alpha have been shown to enhance the effect of IFN-gamma on MSC priming through the production of IDO or PGE2 (page 3 column 2, last paragraph). An increased expression of one or more immunomodulatory factors by the primed MSC compared to MSC that have not been primed by IFN-gamma and TNF-alpha is deemed to be an inherent effect of the combination.
Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).
Regarding claim 6, while Blitzer use MSCs obtained from bone marrow, one of ordinary skill in the art would have been motivated to use MSCs from the salivary gland in the method of Blitzer because Chen teach and suggest that transplantation of MSCs derived from the salivary gland restore salivary gland function in radiation-damaged rat salivary glands (page 4 column 1). Chen also disclose that treatment with BMSCs prevent decline in the salivary flow rate and lymphocytic infiltrations in the salivary glands of NOD mice (model for human research)(page 4, column 2). Therefore, Chen suggest that salivary gland MSCs are a suitable alternative to marrow derived MSCs when treating disfunction of the salivary gland. One of ordinary skill in the art would have had a reasonable expectation of success because Chen teach that MSCs have been found in the salivary gland of patients with salivary gland dysfunction and that such organ specific MSCs may have advantages for treatment of the specific tissue of origin since they would directly act on the target cell. Chen also indicate the MSCs from the salivary gland express the same characteristic MSC markers, are negative for hematopoietic stem cell and salivary gland markers, and can be differentiated into adipogenic, osteogenic and chondrogenic cells (page 4, column 1).
Regarding claims 7, and 9, Blitzer teach that allogeneic transplantation of bone marrow derived stem cells provided an increase in saliva production, promotion of regenerative activity and direct differentiation of the donor stem cells into salivary gland cells (page 3). Chen disclose that in some cases it is not ideal to treat patients with their own MSCs and thus allogeneic MSCs are a beneficial alternative due to non-immunogenic characteristics and low or absent expression of non-major histocompatibility complex (page 4 column 1).
Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use allogeneic MSCs in the method of Blitzer because Blitzer and Chen suggest that they are a suitable alternative to autologous MSCs. One of ordinary skill in the art would have been motivated to use syngeneic MSCs in the method of Blitzer because they are an allogeneic MSC that has been shown to be genetically matched to the patient and thus the optimal type of allogeneic MSC for use in transplantation as it would have less chances of negative side effects.
Regarding claims 10-11, Blitzer disclose that the IFN-gamma used in their method is recombinant human IFN-gamma (page 11, last paragraph). One of ordinary skill in the art would have been motivated with a reasonable expectation of success in using recombinant human TNF-alpha as well because Chen disclose that proinflammatory cytokines such as TNF-alpha have been shown to enhance the effect of IFN-gamma on MSC priming through the production of IDO or PGE2 (page 3 column 2, last paragraph).
Therefore, the combined teachings of Blitzer et al and Chen et al render obvious Applicant’s invention as claimed.
Claim(s) 1-2, 5-9, and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Stem Cells International 2018) in view of Krampera et al (Cell Stem Cell 2021) and Southerland et al (US 2019/0167689).
Regarding claims 1, 5-6 and 12-16, Chen disclose methods for treating xerostomia associated with Sjogren’s disease by administering MSCs to the patient. Chen disclose that proinflammatory cytokines such as TNF-alpha have been shown to enhance the effect of IFN-gamma on MSC priming through the production of IDO or PGE2 (page 3 column 2, last paragraph). Chen disclose that transplantation of MSCs derived from the salivary gland restore salivary gland function in radiation-damaged rat salivary glands (page 4 column 1). Chen also disclose that treatment with BMSCs prevents decline in the salivary flow rate and lymphocytic infiltrations in the salivary glands of NOD mice (model for human research)(page 4, column 2).
Chen do not specifically include an embodiment wherein xerostomia is treated with MSCs that have been pre-treated with a combination of IFN-gamma and TNF-alpha. Chen do not disclose embodiments wherein the xerostomia is associated with graft-versus-host disease (GvHD), age-related, radiation therapy, or chemotherapy.
Krampera disclose that immunological status and inflammatory priming play a pivotal role in regulating MSC functions in vitro and in vivo and that IFN-gamma enhances the intrinsic biological activity of MSCs. Pre-treating MSCs with IFN-gamma, alone or in tandem with TNF-alpha, is a means to rescue MSCs from cell death upon cryopreservation and to enhance the immunosuppressive properties of MSCs (page 1714, column 2). Krampera also teach that MSCs modulate healing and reduce scar stiffness by collagen in radiation therapy induced xerostomia (page 1715, column 2). MSCs are also used to treat GvHD (page 1715).
Southerland disclose that xerostomia is associated with conditions such as Sjogren’s syndrome, old age, GvHD, and medical treatments such as radiation and chemotherapy and can benefit from treatment of the salivary gland (page 6 para 65).
One of ordinary skill in the art would have been motivated to treat xerostomia with MSCs that have been pre-treated with a combination of IFN-gamma and TNF-alpha because Krampera teach and suggest that pre-treating MSCs with IFN-gamma in tandem with TNF-alpha, is a means to enhance the immunosuppressive properties of MSCs (page 1714, column 2). One of ordinary skill in the art would have had a reasonable expectation of success, along with additional motivation, because Chen disclose that proinflammatory cytokines such as TNF-alpha have been shown to enhance the effect of IFN-gamma on MSC priming through the production of IDO or PGE2 (page 3 column 2, last paragraph).
One of ordinary skill in the art would have been motivated to include the treatment of xerostomia associated with other diseases in addition to Sjogren’s, such as GvHD, age related, radiation induced and chemotherapy induced in the method of Chen because Southland teach and suggest that xerostomia patients associated with various diseases and causes can benefit from treatment directed to the salivary gland. One of ordinary skill in the art would have had a reasonable expectation of success because Krampera teach and suggest that MSCs can be used to treat GvHD and radiation induced xerostomia as well.
Regarding claim 2, while Chen, Krampera and Southland are silent with regard to the MSCs having an increased secretion of R-spondin 3 after being treated with a combination of IFN-gamma and TNF-alpha, this effect is deemed to be inherent to the combination.
Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).
Regarding claims 7-9, Chen disclose that in some cases it is not ideal to treat patients with their own MSCs and thus allogeneic MSCs are a beneficial alternative due to non-immunogenic characteristics and low or absent expression of non-major histocompatibility complex (page 4 column 1).
Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to use allogeneic MSCs in the method of Chen because Chen suggest that they are a suitable alternative to autologous MSCs. One of ordinary skill in the art would have been motivated to use syngeneic MSCs in the method of Blitzer because they are an allogeneic MSC that has been shown to be genetically matched to the patient and thus the optimal type of allogeneic MSC for use in transplantation as it would have less chances of negative side effects. One of ordinary skill in the art would have been motivated to use autologous MSCs in xerostomia patients that are not associated with Sjogren’s syndrome because Chen suggest that the disadvantage of autologous MSCs is due to BMSCs and salivary MSCs being defective in patients with pSS (primary Sjogren’s syndrome) (page 4 column 1). One of ordinary skill in the art would have had a reasonable expectation of success because Krampera indicate that autologous MSCs are beneficial as well for therapy (page 1714, Immunological status).
Therefore, the combined teachings of Chen et al, Krampera et al and Southerland et al render obvious Applicant’s invention as claimed.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Paz et al., “Treatment of Radiation-Induced Xerostomia with INF-g Pre Licensed Mesenchymal Stromal Cells (MSCs)”, International Journal of Radiation Oncology Biology Physics, 2022, Vol. 112, No. 5, page e56.
Paz disclose data that strongly supports the feasibility of a first-in-human clinical trial of autologous IFN-ɣ stimulated MSC(M)s to treat radiation induced xerostomia (RIX) and the potential of using human-derived MSC(M)s in future murine studies of RIX.
Le et al., “First Clinical Experiences Using Preconditioning Approaches to Improve MSC-Based Therapies”, Current Stem Cell Reports (2024) 10:1–7.
Le disclose that preconditioning of MSCs are expected to enhance their therapeutic value and to be used to treat xerostomia.
Soler et al., “Treatment with mesenchymal stem cells for xerostomia: A new paradigm in cell therapy”, Integrative Clinical Medicine, 2019, Vol. 3, No. 3, pp. 1-2.
Soler disclose that the three main cause of xerostomia are adverse effects of drugs including chemotherapy, Sjogren syndrome and radiation therapy.
Boland et al., “IFN-g and TNF-a Pre-licensing Protects Mesenchymal Stromal Cells from the Pro-inflammatory Effects of Palmitate”, Molecular Therapy, 2018, Vol. 26, No. 3, pp. 860-873.
Boland disclose the benefits of pretreating MSCs with IFN-gamma and TNF-alpha in protecting immunosuppressive function.
Gong et al., “Murine embryonic mesenchymal stem cells attenuated xerostomia in Sjögren-like mice via improving salivary gland epithelial cell structure and secretory function”, Int J Clin Exp Pathology, 2020;13(5):954-963.
Gong disclose the chronic proliferation of T and B cells secrete interferon gamma and tumor necrosis factor alpha which also induce Fas expression and mediate the apoptosis of salivary gland cells (SGEC).
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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