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 .
Election/Restrictions
Applicant’s election without traverse of Group II claims 1, 5-7, 11-16, 18, 21, and 23-25 in the reply filed 30 Sep 2025 is acknowledged.
The restriction of claims in Groups I-IV is withdrawn. Invention Groups I, III, and IV drawn to claims 1, 5-7, 11-16, 18, 21, and 23-25 are rejoined and examined with elected Group II.
Applicant’s species election without traverse of cytokine release syndrome, drawn to claim 12; anti-cytokine therapy, drawn to claim 15; anti-IL6R, drawn to claim 16; IL-2, drawn to claim 18; intravenous, drawn to claim 21; and paclitaxel, drawn to claims 23-25, in the reply filed 30 Sep 2025 is acknowledged.
Based on the results of the search, the species election requirement between the species of proinflammatory cytokine, drawn to claim 18, has been withdrawn.
Claims 2-7 and 9-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being to no allowable generic or linking claim. Election was made without traverse in the reply filed 30 Sep 2025.
Claims 8, 17, 19-20, and 22 are canceled. Claims 1, 11-16, 18, 21, and 23-25 are pending and under consideration.
Claim Objections
Claims 1, 16, and 18 is objected to because they contain abbreviations without definition of the full term and without antecedent basis.
Claim 13 should be corrected to say, “The method of claim 1, wherein conditioned media is administered to said subject.” or a similar phrase.
Claim 14 should be corrected to say “administering” rather than “administrating” to be consistent with the terminology of the other claims.
Claim 18 should be corrected to say “said treatment”, “said method of treating” or a similar phrase instead of “said treating”.
Appropriate correction is required for all claim objections.
Claim Interpretation
For the purposes of examination, the abbreviation “MSC” of claim 1 is interpreted to be mesenchymal stem cells consistent with the definition provided in the Specification par. 6.
Claim Rejections - 35 USC §112
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 are rejected under 35 U.S.C. §112(a) for the following reasons. The specification is enabling for a method of treating or ameliorating cytokine storm in a patient comprising administration of mesenchymal stem cells (MSC) contacted with paclitaxel, cisplatin, or gemcitabine or conditioned media of said MSC, wherein administration is performed by systemic administration, depot injection to an extravascular compartment, or intratracheal administration. The specification, however, does not reasonably provide enablement for prevention of cytokine storm, all routes of administration, or all classes of chemotherapeutics. The specification does not enable any person skilled in the art to which it pertains to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states that “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) 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 23-25 pertain to a method of treating, ameliorating, or preventing a cytokine storm. These claims are broad in that they encompass prevention of cytokine storm. Applicant provides examples using the conditioned media of MSC contacted with paclitaxel, cisplatin, or gemcitabine to treat cytokine storm (Fig. 1-11). In the examples, cytokine storm was induced by intratracheal delivery of lipopolysaccharides (LPS) and subsequently treated with conditioned media. However, this is working example of treatment, not prevention. To demonstrate prevention, a working example would require that the MSC or conditioned media thereof be administered before or very shortly after induction of cytokine storm and that the likelihood of onset of severe symptoms and underlying pathological features of cytokine storm be reduced. Alternatively, the specification could provide guidance as to how to predict the onset of cytokine storm and explain how the invention addresses those predicted features. A definition for prevention is provided in the Specification, par. 110; however, the specification does not discuss how prevention is achieved. In the absence of a working example, a skilled artisan may look to the art for guidance as to the predictability of preventing cytokine storm. However, at the time of filing, there were no preventative strategies available for cytokine storm, even for scenarios where the onset of cytokine storm is predictable, such as in consequence to cancer immunotherapy (E. Huarte, et al., Clinical Cancer Research, 2020, Introduction). Given the lack of available preventative strategies, a skilled artisan would be unable to predict that the method of claim 1 could successfully prevent cytokine storm. Therefore, the specification provides enablement for treatment and amelioration of cytokine storm but not prevention.
Claims 1, 11-16, 18, 21, and 23-25 additionally pertain to administering a pharmaceutical composition of MSC 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 intraperitoneal (I.P.) injection or by intratracheal (I.T.) instillation (Fig. 6 and 7). 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. Given the variability of success in the working examples, a skilled artisan would be unable to predict success of other routes of administration. 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, bolus or infusion volumes, and more, 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 (J. Galipeau, 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.
Claims 1, 11-16, 18, 21, and 23-25 additionally pertain to administering MSC contacted with chemotherapy or conditioned media thereof. These claims are broad in that chemotherapeutics are not a genus of structurally or mechanistically similar drugs and are only related by their effect on cancer. Chemotherapeutics represent dozens of classes of structurally distinct compounds that can inhibit cancer cells through any possible mechanism, and many chemotherapeutics are highly pleiotropic. Applicant provides working examples of preconditioning MSC with paclitaxel, cisplatin, or gemcitabine for the treatment of cytokine storm (Fig. 1-11). These three chemotherapeutic drugs represent three structurally and mechanistically distinct classes – taxanes, platinum-based compounds, and pyrimidine prodrugs, respectively. Of the working examples, only paclitaxel is shown to consistently recover disease parameters in a mouse cytokine storm model, whereas cisplatin has a modest effect in some results (Fig. 3, 4A) and no effect in other results (Fig. 2). No quantitative data are shown for gemcitabine. Given the variability of results and lack of general quality running through the three different classes of drugs in the working examples, a skilled artisan would be unable to predict the success of a new class of chemotherapeutic using the method of claim 1. Applicant does provide additional examples of chemotherapeutics and anti-cancer agents to activate MSC that cross structurally and mechanistically distinct classes of chemotherapeutics, including 5-fluoruracil (a thymidylate synthase inhibitor), cyclophosphamide and dacarbazine (alkylating agents), doxorubicin and epirubicin (anthracyclines), methotrexate (an antifolate), docetaxel (a taxane), viorelbine (a vinca alkaloid) (Specification par. 63 and par. 112). Applicant additionally cites WO 2020049552 A1 (Table 1) for examples of chemotherapeutics that activate MSC. Note that both lists include anti-cancer agents not considered in the art to be chemotherapeutics, but are rather biologics or radiation therapy. Even though these lists of chemotherapeutics are provided, neither the specification nor the incorporated reference offer guidance as to what properties or effects are required (i.e. a mechanism) for a chemotherapeutic to enhance MSC or conditioned media thereof to treat cytokine storm. The art at the time of filing teaches that the immunomodulatory properties of MSC are not constitutive and require priming (or activation) (G. Almeida-Porada, et al., Molecular Therapy - Methods & Clinical Development, 2020, pg. 208-209 – herein Almeida-Porada). Almeida-Porada also teaches that simple factors such as concentration of the activating molecules and duration of exposure can result in an undesirable biological response in MSC and that the mechanism underlying these responses remains unclear. Therefore, given the lack of guidance from the specification or the art, even a highly skilled artisan would be unable to predict whether a new class of chemotherapeutic could enhance the ability of MSC or conditioned media thereof to treat cytokine storm, even if the pharmacological mechanism of the drug in cancer was very well characterized. Therefore, the specification provides enablement for paclitaxel, cisplatin, and gemcitabine but not all chemotherapeutics.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. §103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 11-16, 18, 21, and 23-25 are rejected under 35 U.S.C. §103.
Claims 1, 11-13, 21, and 23-25 are 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), Mirzapoiazova (T. Mirzapoiazova, et al., Eur Respir J, 2007), and Rathinam (V.A.K. Rathinam, et al., Nat Immunol, 2019).
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, pg. 8). 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 23-25 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 23-25, 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).
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. Therefore, claims 1, 11-13, 21, and 23-25 are rejected as obvious in view of the prior art.
Claims 14-16 are rejected under 35 U.S.C. §103 as unpatentable over Gonzalez, Pessina, and Mirzapoiazova as applied to claims 1, 11-13, 21, and 23-25 above and further in view of Le (R.W. Le, et al., The Oncologist, 2017).
The use of MSC, MSC conditioned media, and chemotherapy to treat cytokine storm are taught by Gonzalez, Pessina, and Mirzapoiazova as discussed in the rejection of claims 1, 11-13, 21, and 23-25 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. Therefore, claims 14-16 are rejected as obvious in view of the prior art.
Claim 18 is rejected under 35 U.S.C. §103 as unpatentable over Gonzalez, Bogatcheva, Petrella, and Mirzapoiazova as applied to claims 1, 11-13, 21, and 23-25 above, and in further view of Suntharalingam (G. Suntharalingam, et al., NEJM, 2006).
The use of MSC, MSC conditioned media, and chemotherapy to treat cytokine storm are taught by Gonzalez, Pessina, and Mirzapoiazova as discussed in the rejection of claims 1, 11-13, 21, and 23-25 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.
Conclusion
No claim is allowed.
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/Eric B Wright, PhD/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632