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 .
Claim Status
Applicant’s amendments to the claims filed 12 Apr 2026 are acknowledged. Claims 8-10, 17, 19-20, and 22 are canceled. Claims 26 and 27 are added. Claims 2-7 are withdrawn. Claims 1, 11-16, 18, 21, and 23-27 are under consideration.
Claim Objections
All claim objections are moot due to amendment to the claims.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL. — The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1, 11-16, 18, 21, and 23-25 remain rejected and newly added claim 26 is rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for,
a method of treating or ameliorating cytokine storm in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising mesenchymal stem cells (MSC) contacted with paclitaxel, cisplatin, or gemcitabine or conditioned media of said MSC, wherein the composition is administered systemically, by depot injection to an extravascular compartment, or by intratracheal administration,
does not reasonably provide enablement for delivery of the pharmaceutical composition by other routes of administration. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. The rejection is amended as necessitated by amendment to the claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word ‘undue’, not ‘experimentation.’” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). When determining whether a specification meets the enablement requirement, some of the factors to be analyzed are: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill in the art, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, and (8) whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is undue (Wands). While all of these factors are considered, those sufficient for establishing a prima facie case are discussed below.
Claims 1, 11-16, 18, 21, and 23-26 pertain to administering a pharmaceutical composition comprising MSC contacted with paclitaxel, cisplatin, gemcitabine, or conditioned media thereof to a patient. These claims are broad in that the term "administering" includes any possible route of administration. The specification provides working examples comparing routes of administration of MSC conditioned media by systemic administration via intraperitoneal (I.P.) injection or local administration to the lung by intratracheal (I.T.) instillation to resolve lung inflammation and respiratory rate (Fig. 6 and 7). The specification provides a list of routes of administration (par. 117). This list is followed by examples of how the pharmaceutical composition may be formulated (par. 118-125). Both the list of routes of administration and the formulations, however, act as non-exhaustive lists of examples and do not provide guidance to a skilled artisan as to how to avoid undue experimentation when making or using the invention as claimed when evaluating other routes of administration. Without specific guidance, a skilled artisan would be faced with undue experimentation to attempt to make and use the claimed invention, as the artisan must test an enormous variety of open-ended formulation compositions, numbers of cells, processing steps for the conditioned media, media compositions, delivery routes, and bolus or infusion volumes, then must still evaluate the ability of the new composition and delivery route to treat cytokine storm.
Guidance for MSC and conditioned media is provided in the art at the time of filing. The most common routes of administration for MSC are intravenous, depot injection to an extravascular compartment, and direct administration to an afflicted/target organ et al., Cytotherapy, 2021, pg. 370-herein Galipeau). Intravenous and depot delivery are the most relevant for systemic disease, although cytokine storm may originate from a particular organ, such as in the infection model of the working example of the immediate application. It is well established that MSC can be far removed from the site of injury and still display beneficial effects; however, the secreted products from MSC, such as extracellular vesicles, must be able to reach circulation to achieve these effects (Galipeau, pg. 369-370). Therefore, a skilled artisan would be unable to predict successful treatment of cytokine storm when chemotherapy-contacted MSC or conditioned media thereof are administered via routes that cannot easily reach systemic circulation, such as oral, ocular, topical, transdermal, or rectal administration (S.C. Gad and C.B. Spainhour, CRC Press, 2018, pg. 68-90). Therefore, the specification provides enablement for intravenous delivery, depot injection to an extravascular compartment, direct administration to an afflicted/target organ, and intratracheal instillation but not for all routes of administration.
The rejection of claims 1, 11-16, 18, 21, and 23-25 under 35 U.S.C. § 112(a) based on scope of enablement with regard to prevention of cytokine storm and breadth of chemotherapeutics are moot due to amendment to the claims. The rejection of claims 1, 11-16, 18, 21, and 23-25 under 35 U.S.C. § 112(a) based on scope of enablement with regard to route administration is maintained.
In response to the rejection of claims 1, 11-16, 18, 21, and 23-25 under 35 U.S.C. § 112(a) with regard to route of administration, Applicant argues that intraperitoneal (IP) injection was effective, and is therefore enabling for systemic routes of administration. Applicant disagrees with the assertion stated in the rejection that, " In the working examples, I.T. instillation of conditioned media from paclitaxel-contacted MSC resolved lung inflammation (Fig. 6) and respiratory rate (Fig.7), whereas I.P. injection was not successful." Applicant additionally notes that while intratracheal (IT) administration was superior to IP, that IP still ameliorated cytokine storm.
The assertion that IP treatment was unsuccessful was based on H&E images presented in Fig 6, which show that the airways of IP-treated animals remain heavily infiltrated with inflammatory cells, and Fig 7, which shows a statistically significant difference between IT-treated and untreated animals but not between IP-treated and untreated animals. However, it is additionally noted that CT images presented in Fig 6 show reduced edema in IP-treated animals compared to untreated, and data presented in Fig 7 show that respiratory rate of IP-treated animals is not different than healthy, uninfected animals. Note that the difference in response to IP versus IT administration was merely to point out variability, not to argue that systemic administration via IP injection is not enabled. However, based on persuasive arguments by Applicant and upon further review of data presented in the specification, the assertion that IP treatment was unsuccessful is withdrawn. Based on the working examples for IP injection and IT administration provided, a skilled artisan would recognize that systemic and local routes, respectively, of administration are generally enabled.
Applicant additionally notes that many patent applications "will demonstrate only 1 method of administration and enablement will be acknowledged for all routes of administering because there is no reason to suggest that other routes would not work." However, additional routes of administration that would have barriers to delivering MSC or their secreted products to the site of disease are not enabled as previously described in the rejection of claims 1, 11-16, 18, 21, and 23-25 under 35 U.S.C. § 112(a). For a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art (in view of level of skill, state of the art and the information in the specification) would expect the claimed genus could be used in that manner without undue experimentation. Proof of enablement will be required for other members of the claimed genus only where adequate reasons are advanced by the examiner to establish that a person skilled in the art could not use the genus as a whole without undue experimentation. See MPEP § 2164.02. A reasonable basis to question the enablement is provided for the claimed invention. A mere statement that other routes of administration are enabled is insufficient to overcome the rejection. Therefore, applicant's arguments are not found persuasive and the rejection is maintained with regard to route of administration.
Claims 1, 11-16, 18, 21, and 23-27 are newly rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed had possession of the claimed invention. This rejection made in the interest of compact prosecution based on an alternative interpretation of the newly added limitation to claim 1, which recites "wherein said pharmaceutical composition is not cytotoxic to said subject". In the alternative interpretation, that the pharmaceutical composition is not cytotoxic at the level of individual cells.
Claim 1 is amended to recite, "wherein said pharmaceutical composition is not cytotoxic to said subject" in lines 6-7. This claim limitation recites elements without support in the original disclosure. A written-description question often arises when an applicant, after filing a patent application, subsequently adds "new matter" not present in the original application; In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 608.04(a). Claims 11-16, 18, 21, and 23-27 are included in this rejection as they depend from claim 1 and do not recite additional limitations to remedy the matter. The only recitation of the term "cytotoxic" in the specification is in reference to cytotoxic T cells (par. 103), which is in reference to the activity of a subset of T cells, not to the claimed pharmaceutical composition.
Sazonova (E.V. Sazonova, et al., Cell Death Discovery, 2022) teaches that the term cytotoxicity, as used in the art, refers specifically to cell death (Introduction p. 1). Death of a large number of cells in a patient can lead to an aggregate effect resulting in tissue- or organ-level toxicity. Measurement of cytotoxicity must differentiate between cytostatic effects, such as inhibition of metabolism or cell proliferation, and cell death mechanisms, such as apoptosis (Introduction p. 1). Toxicity at the organ or organism level does not require cell death. A pharmaceutical composition can, therefore, be cytotoxic to individual cells but not rise to an overt toxic effect in a subject.
The specification provides in Example 3 that paclitaxel-activated MSC are not toxic at the organ level in several examined organs, and it is thus concluded that the composition is safe and non-toxic (par. 150). However, the specification does not contemplate or describe assessment of cytotoxicity in individual cells. Pessina (A. Pessina, et al. PLoS One, 2011, reference U in PTO-892 filed 16 Jan 2026) teaches that MSC uptake and release paclitaxel and release paclitaxel-loaded exosomes that are cytotoxic to endothelial cells in vitro (Results p. 5 and Fig. 4). Therefore, a skilled artisan would expect that the composition in Example 3 would also be cytotoxic.
The specification is silent with regard to the mechanism by which MSC contacted with paclitaxel, cisplatin, or gemcitabine, or the conditioned media thereof, suppresses cytokine storm. There is nothing of the record to indicate the composition is not cytotoxic. Therefore, a skilled artisan would not recognize that the applicant was in possession of the invention as claimed.
Newly added claim 26 is rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed had possession of the claimed invention.
Newly added claim 26 recites, "wherein said pharmaceutical composition is devoid of said chemotherapy". This claim limitation recites elements without support in the original disclosure. A written-description question often arises when an applicant, after filing a patent application, subsequently adds "new matter" not present in the original application; In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 608.04(a).
No basis is found in the specification that MSC contacted with paclitaxel, cisplatin, or gemcitabine or the conditioned media thereof is devoid of paclitaxel, cisplatin, or gemcitabine. The specification describes preparation of MSC contacted with paclitaxel, cisplatin, or gemcitabine (par. 135). However, the specification does not contemplate any steps that would remove the paclitaxel, cisplatin, or gemcitabine from the MSC before use as a therapeutic. To generate conditioned media from MSC contacted with paclitaxel, cisplatin, or gemcitabine, media is removed and MSC are cultured in serum-free media (par. 135). Pessina (A. Pessina, et al. PLoS One, 2011, reference U in PTO-892 filed 16 Jan 2026) teaches that MSC uptake and slowly release paclitaxel (Discussion p. 8). Based on the teachings of Pessina, a skilled artisan would expect that the MSC would release uptaken paclitaxel, cisplatin, or gemcitabine into the serum-free conditioned media.
Furthermore, no contemplation or description is provided for whether the amount of paclitaxel, cisplatin, or gemcitabine was ever measured to determine if the pharmaceutical composition is devoid of chemotherapy. Therefore, a skilled artisan would not recognize that the applicant was in possession of the invention as claimed.
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, 21, and 23-25 remain rejected and newly added claim 26 is rejected under 35 U.S.C. § 103 as being unpatentable over Gonzalez (J. Gonzalez, US 2017/0166869 A1, 2017) in view of Pessina (Pessina, et al. PLoS One, 2011) and Mirzapoiazova (T. Mirzapoiazova, et al., Eur Respir J, 2007), and as evidenced by Rathinam (V.A.K. Rathinam, et al., Nat Immunol, 2019). The rejection is amended as necessitated by amendment to the claims.
Gonzalez teaches priming (i.e., activating) mesenchymal stem cells (MSC) to improve their immunomodulatory activity to treat or ameliorate cytokine storm (claim 1) and acute respiratory distress syndrome (ARDS) (par. 6, 7, and 18). Gonzalez additionally teaches that primed MSC are more effective at treating cytokine storm than unprimed MSC (Example 1). Gonzalez additionally teaches administration of a therapeutically effective amount of primed MSC or conditioned media thereof (claim 1) (par. 10 and 18). While Gonzalez teaches priming of MSCs using a cytokine, Gonzalez does not teach priming of MSC using chemotherapy.
However, Pessina teaches priming MSC with paclitaxel (claims 1 and 23-25) (abstract). Pessina demonstrates that MSC can be primed in vitro with paclitaxel, then primed MSC release paclitaxel in a pharmacologically active form in their conditioned media (Fig. 1-4). Pessina additionally demonstrates that MSC primed with paclitaxel are more potent in vivo than unprimed MSC or free paclitaxel at an equivalent concentration (Fig. 5). Pessina suggests that the MSC may enhance the potency of paclitaxel in vivo by slowly releasing paclitaxel in close proximity to the effected cells (Discussion, p. 8). Pessina, instead, teaches that paclitaxel released from MSC merely inhibits proliferation of cancer cells in vitro and limits tumor growth in vivo (Results pp. 5-6 and Fig. 4-5). Furthermore, Pessina teaches that paclitaxel released from MSC is cytotoxic to endothelial cells in vitro (Results p. 5 and Fig. 4), but is silent with regard to toxicity in vivo. Therefore, there is nothing of the record to indicate that the composition taught by Pessina is cytotoxic in vivo. The teachings of Pessina, however, are directed to cancer therapy and not cytokine storm.
However, Mirzapoiazova teaches use of taxol (another term for paclitaxel, CAS Registry Number 33069-62-4) to treat cytokine storm (claims 1 and 23-25) (abstract). Mirzapoiazova uses a lipopolysaccharide (LPS)-induced acute lung injury model, and Rathinam teaches that LPS induces cytokine storm (pg. 527, third par.); therefore, the mouse model of Mirzapoiazova serves as a model of cytokine storm.
Taken together, each element of claims 1, 11-13, 21, and 23-26 is taught in the prior art performing the same function separately as in the combination of the claimed invention. The only difference between the claimed invention and the prior art is the lack of actual combination of the elements in a single embodiment in a prior art reference. The priming step of Gonzalez to improve immunomodulatory function of MSC or conditioned media thereof may be achieved by priming with paclitaxel as taught by Pessina. The paclitaxel-primed MSC or their conditioned media may be administered for the treatment of cytokine storm as taught by Gonzalez and Mirzapoiazova.
Claims 11-13, 21, and 23-26, which depend from claim 1, do not introduce additional limitations that are not met by the teachings of Gonzalez, Pessina, and Mirzapoiazova. Claim 11 introduces the limitation “... wherein said subject does not suffer from lung fibrosis.” The use of paclitaxel to treat cytokine storm as taught by Mirzapoiazova is performed in an acute model of lung injury that does not induce fibrosis (Fig 1 and Results, first par.). Claim 12 introduces the limitation “...cytokine release syndrome” (CRS). Applicant notes in the specification that “... cytokine storm is the immediate onset of CRS (par. 86); therefore, treatment of cytokine storm necessarily treats CRS. Claim 13 introduces the limitation “... administering said conditioned media”, which is included in the scope of claim 1. Claim 21 introduces the limitation, “... wherein the composition is administered by ... intravenous ... administration.” Gonzalez teaches intravenous administration of MSC therapy (Example 1, par. 24). Claims 23-25 introduce the limitation, “... wherein said chemotherapy is ... paclitaxel.” Pessina teaches use of paclitaxel to prime MSC (abstract) and Mirzapoiazova teaches use of paclitaxel to treat cytokine storm (abstract).
Newly added claim 26 introduces the limitation "wherein said pharmaceutical composition is devoid of said chemotherapy". As noted above in the rejection of claim 26 under 35 U.S.C. § 112(a), basis for what is regarded as devoid is not found in the specification. Therefore, the broadest reasonable interpretation is of the claim limitation is taken; under one alternative interpretation, the MSC are treated with paclitaxel, gemcitabine, or cisplatin, then the cells are washed and administered without additional chemotherapy added to the composition. Pessina teaches administration of paclitaxel-treated MSC after several washes (Results p. 2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the method of using primed MSC or conditioned media thereof to treat cytokine storm as taught by Gonzalez by priming MSC with paclitaxel as taught by Pessina and with the method of using paclitaxel to treat cytokine storm as taught by Mirzapoiazova to arrive at a method of treating cytokine storm using paclitaxel-primed MSC or conditioned media thereof. One would be motivated to make such a combination because Pessina teaches that priming MSC with paclitaxel in vitro enhances the pharmacological activity of paclitaxel by slow release of the drug in proximity to target diseased cells. One would have a reasonable expectation of success in making the combination as primed MSC, conditioned media from primed MSC, and paclitaxel are each taught in the prior art to treat cytokine storm in isolation, and a combination of MSC and paclitaxel in a manner that enhances the activity paclitaxel would be expected to be more effective than MSC or paclitaxel alone.
Claims 14-16 remain rejected under 35 U.S.C. § 103 as unpatentable over Gonzalez, Pessina, and Mirzapoiazova as applied to claims 1, 11-13, 21, and 23-26 above and further in view of Le (R.W. Le, et al., The Oncologist, 2017).
Gonzalez, Pessina, and Mirzapoiazova teach a method of administering MSC contacted with paclitaxel or conditioned media thereof to treat cytokine storm as discussed in the rejection of claims 1, 11-13, 21, and 23-26 under 35 U.S.C. § 103 above.
The references do not teach combination with an additional drug or therapy, as required by claim 14, that drug or therapy being an anti-cytokine therapy, as required by claim 15, or that anti-cytokine therapy being an anti-IL6R antibody, as required by claim 16.
However, Le teaches use of the anti-interleukin 6 receptor antibody (anti-IL6R) tocilizumab for the treatment of cytokine release syndrome (CRS, aka cytokine storm) (abstract). Le teaches that tocilizumab in an FDA-approved therapy based on efficacy in clinical trial results in patients with chimeric antigen receptor T cell-induced CRS (abstract). Le does not teach use of MSC, MSC conditioned media, or paclitaxel to treat cytokine storm.
Each element of claims 14-16 is taught in the prior art performing the same function separately as in the combination of the claimed invention. The only difference between the claimed invention and the prior art is the lack of actual combination of the elements in a single embodiment in a prior art reference. Tocilizumab is an FDA-approved treatment for cytokine storm as a standalone therapy. As discussed above, MSC, MSC conditioned media, and paclitaxel are each taught as treatments for cytokine storm.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine MSC primed with paclitaxel or conditioned media thereof as taught by Gonzalez, Pessina, and Mirzapoiazova with the anti-IL6R antibody tocilizumab as an additional anti-cytokine therapy to treat cytokine storm in a patient. One would have been motivated to make the combination because the clinical efficacy of primed MSC and paclitaxel have not been tested, but tocilizumab has been demonstrated to be an effective therapy in patients, increasing the likelihood of success by combining multiple modes of therapy. One would have a reasonable expectation of success in making the combination as each of primed MSC, conditioned media from primed MSC, paclitaxel, and tocilizumab have been taught in vivo to treat cytokine storm and can be expected to be more effective in combination.
Claim 18 remains rejected under 35 U.S.C. §103 as unpatentable over Gonzalez, Bogatcheva, Petrella, and Mirzapoiazova as applied to claims 1, 11-13, 21, and 23-26 above, and in further view of Suntharalingam (G. Suntharalingam, et al., NEJM, 2006).
Gonzalez, Pessina, and Mirzapoiazova teach a method of administering MSC contacted with paclitaxel or conditioned media thereof to treat cytokine storm as discussed in the rejection of claims 1, 11-13, 21, and 23-26 under 35 U.S.C. § 103 above.
Mirzapoiazova additionally teaches partial restoration in respiratory parameters, including neutrophil infiltration to the lungs and pulmonary edema, upon treatment of cytokine storm with paclitaxel (Results Fig 2 and 4). The references do not teach reduction in proinflammatory cytokines in cytokine storm as required by claim 18.
However, Suntharalingam teaches that proinflammatory cytokines increase dramatically from normal physiological levels during cytokine release syndrome (aka cytokine storm) (Results pg. 1026, Fig. 3, and Supplementary Appendix, first table). Suntharalingam additionally teaches that several respiratory parameters are increased during cytokine storm, including tachypnea (increased breath rate), decreased partial pressure of arterial oxygen (PaO2), pulmonary infiltrates on chest radiography, use of accessory muscles to breath, and dyspnea (shortness of breath) (Results first par. on pg. 1019, fourth par. on pg. 1022, and Table 3). Suntharalingam additionally teaches that proinflammatory cytokine levels and respiratory parameters recovered back to normal levels after treatment. Suntharalingam does not teach use of MSC, MSC conditioned media or exosomes, or chemotherapy to treat cytokine storm.
Each element of claim 18 is taught in the prior art performing the same function separately as in the combination of the claimed invention. The only difference between the claimed invention and the prior art is the lack of actual combination of the elements in a single embodiment in a prior art reference. Cytokine storm, by definition, is an increase in proinflammatory cytokines; therefore, any successful treatment for cytokine storm would necessarily result in a decrease in the levels of proinflammatory cytokines from their peak values. Suntharalingam observed in their clinical trial of cytokine storm induction increase proinflammatory cytokines from normal during cytokine storm and restoration to normal following treatment. Suntharalingam and Mirzapoiazova observed disturbances in respiratory parameters in concert with cytokine storm and total or partial restoration in response to markedly different treatments.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine MSC primed with paclitaxel or conditioned media thereof to treat cytokine storm as taught by Gonzalez, Pessina, and Mirzapoiazova with the result of reducing pro-inflammatory cytokine levels and improving respiratory parameters as taught by Mirzapoiazova and Suntharalingam. One would be motivated to make the combination because increase in proinflammatory cytokine levels and respiratory distress are key features in cytokine storm; therefore, reduction in proinflammatory cytokines and resolution of respiratory parameters to normal would mark successful treatment of cytokine storm. One would have a reasonable expectation of success as primed MSC, conditioned media from primed MSC, and paclitaxel are each taught in the prior art to treat cytokine storm in isolation, and therefore can be reasonably expected to reduce proinflammatory cytokine levels and restore respiratory parameters in combination.
Claim 27 is newly rejected under 35 U.S.C. § 103 as unpatentable over Gonzalez, Pessina, and Mirzapoiazova as applied to claims 1, 11-13, 21, and 23-26 above and further in view of Ionescu (L Ionescu, Am J Physiol Lung Cell Mol Physiol, 2012) and as evidenced by Rathinam (V.A.K. Rathinam, et al., Nat Immunol, 2019).
Gonzalez, Pessina, and Mirzapoiazova teach a method of administering MSC contacted with paclitaxel or conditioned media thereof to treat cytokine storm as discussed in the rejection of claims 1, 11-13, 21, and 23-26 under 35 U.S.C. § 103 above.
The references do not local administration of MSC or conditioned media thereof to the lungs as required by claim 27.
However, Ionescu teaches administration of MSC or MSC conditioned media by intratracheal administration (local administration to the lung) for the treatment of lipopolysaccharide (LPS)-induced acute lung injury (Abstract and Results p. L970). As noted above, Rathinam teaches that LPS induces cytokine storm (pg. 527, third par.); therefore, LPS-induced acute lung injury serves as a cytokine storm model. Ionescu teaches that MSC and MSC conditioned media attenuated LPS-induced immune cell infiltration to the lung, lung permeability (Results pp. L970-L971 and Fig. 2 and 3B-C). Ionescu further teaches that in vitro priming of MSCs would allow for combination of the advantages of both cell and small molecule therapy (Discussion p. L975)
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the method of administering MSC contacted with paclitaxel or conditioned media thereof to treat cytokine storm as taught by Gonzalez, Pessina, and Mirzapoiazova with administration of MSC or MSC conditioned media locally to the lung as taught by Ionescu to arrive at the claimed invention. One would be motivated to make the combination as Ionescu teaches that in vitro priming of MSCs would allow for combination of the advantages of both cell and small molecule therapy. One would have a reasonable expectation of success in making the combination as Ionescu demonstrates that MSC and MSC conditioned media resolves immune cell infiltration and edema in a cytokine storm model.
The rejection of claims 1, 11-16, 18, 21, and 23-25 under 35 U.S.C. § 103 is maintained.
Applicant argues that the mechanism taught by Gonzalez, Pessina, and Mirzapoiazova is based on delivery of paclitaxel to the patient/lung, whereas the instant composition does not. Applicant argues instead that that paclitaxel merely activates the MSC and that the composition does not contain paclitaxel, and is, therefore, not cytotoxic to the subject. Applicant additionally argues that the MSC taught by Pessina are cytotoxic to cancer cells and that the "taxol of Mirzapoiazova is clearly toxic" and, therefore, the references do not teach a non-cytotoxic composition. On the basis of these arguments, Applicant concludes that the amendment to claim 1 to include the limitation, "wherein said pharmaceutical composition is not cytotoxic to said subject" renders claim 1 and the claims that depend from claim 1 non-obvious over the cited art.
However, Pessina (A. Pessina, et al. PLoS One, 2011, reference U in PTO-892 filed 16 Jan 2026) does not teach that paclitaxel released from MSC are toxic to cancer cells. Pessina, instead, teaches that paclitaxel released from MSC merely inhibits proliferation of cancer cells in vitro and limits tumor growth in vivo (Results pp. 5-6 and Fig. 4-5). Furthermore, Pessina teaches that paclitaxel released from MSC is cytotoxic to endothelial cells in vitro (Results p. 5 and Fig. 4), but is silent with regard to toxicity in vivo. Therefore, there is nothing of the record to indicate that the composition taught by Pessina is cytotoxic in vivo.
Furthermore, there is no basis for the conclusion that the paclitaxel treatment taught by Mirzapoiazova (T. Mirzapoiazova, et al., Eur Respir J, 2007, reference V in the PTO-892 filed 16 Jan 2026) is cytotoxic in the subjects. Paclitaxel is not cytotoxic in all circumstances. At low concentrations, such as those used by Mirzapoiazova, paclitaxel merely inhibits microtubule dynamics and induces cell cycle arrest, neither of which necessarily cause cytotoxicity (Discussion, pp. 432 and 434). There is nothing of the record to indicate that the paclitaxel taught by Mirzapoiazova induces cytotoxicity.
The conclusion that the methods taught by Pessina and Mirzapoiazova both rely on cytotoxicity as a mechanism of action is unfounded. Applicant's arguments are not found persuasive. Therefore, the rejection of claims 1, 11-16, 18, 21, and 23-25 under 35 U.S.C. §103 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.
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Eric B Wright, PhD
Examiner
Art Unit 1632
/Eric B Wright/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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