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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner in form PTO-892, they have not been considered.
Claim Objections
Claims 2, 3, 9-11, 13, and 18 are objected to because of the following informalities:
Regarding claims 2, 3, 9-11, and 13, the first instance of any abbreviation recited in the claims should be accompanied by the full, written out term, then the abbreviation may be used alone thereafter.
Regarding claim 18, “generated peripheral” should be corrected to “generated from peripheral”.
Appropriate correction is required.
Claim Interpretation
For the purposes of examination, claim 5 is interpreted to mean that an antibody is administered to one of said inflammatory markers recited in claim 3.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 5-7 and 9 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention. Claim 3, from which claims 5-7 and 9 ultimately depend, recites “wherein said inflammatory markers are selected from the group consisting of”, referring to said inflammatory markers in the plural. Whereas claim 5 recites, “said inflammatory marker” in the singular. It is unclear what inflammatory marker(s) the antibody of claim 5 is intended to target because claim 3 is drawn to a group of inflammatory markers.
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 1-20 are rejected under 35 U.S.C. §112(a) for the following reasons. The specification is enabling for a method of treating chronic obstructive pulmonary disease (COPD) comprising the steps of:
obtaining a patient suffering from COPD,
assessing inflammatory markers in said patient,
administering to said patient a therapeutic dose of myeloid derived suppressor cells (MDSC) derived from umbilical cord blood or bone marrow and treated with interleukin-3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) prior to administration, and
assessing patient pathology and inflammatory markers and adjusting dose and/or frequency of myeloid derived suppressor cells being administered.
The specification, however, does not reasonably provide enablement for all MDSC regardless of tissue sourcing, characterization, or pre-treatment prior to 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 or 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, “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 1-20 are drawn to treatment of chronic obstructive pulmonary disease (COPD) by administration of myeloid-derived suppressor cells (MDSC) and adjustment of cell dose and dose frequency based on pre- and post-treatment patient pathology and levels of inflammatory markers. Claims 5-7 and 9 are further drawn to co-administration of MDSC with an antibody targeting one the inflammatory markers recited in claim 3. The nature of the invention relates to treatment of COPD by utilizing the immunosuppressive phenotype of MDSC to reduce inflammation in the lungs to alleviate symptoms of COPD.
With regard to administration of MDSC to treat COPD (claims 1-20), the claims are broad in that they encompass any embodiment of MDSC regardless of their tissue origin, characterization, or pre-treated prior to administration to a patient with COPD.
The specification provides a working example wherein mice treated with elastase to model COPD are administered MDSC derived from umbilical cord blood and pre-treated with IL-3 and GM-CSF, resulting in decreased inflammation as measured by infiltration of neutrophils to the lungs (Fig. 1 and par. 31). Aside from the tissue of origin, details of how the MDSC were derived and characterized in the working example are not provided.
An additional example of using MDSC to treat COPD is found in the art. Cruz (F.F. Cruz, et al. Resp Phys & Neurobio. 2012) teaches administration of cells comprising 50.1% CD11b-positive/CD14-negative cells for the treatment of chronic obstructive pulmonary disease (COPD) (Abstract, Materials and Methods section 2.1, and Results first par.). The specification teaches that the major population of MDSC, polymorphonuclear MDSC (PMN-MDSC), are similar to neutrophils and are CD11b-positive and CD14-negative (par. 27). Bronte (V. Bronte, et al. Nat Commun. 2016), Zhang (W. Zhang, et al. J Transl Med, 2021) supports that the CD11b-positive/CD14-negative cells of Cruz are MDSC. MDSC are not a distinct cell type identified by a specific path of differentiation, but rather represent a heterogenous population of immature myeloid cells sharing an immunosuppressive phenotype (Bronte p. 2). Given that Cruz observed reduced inflammation in a mouse model of COPD using a mixed immune cell population, the CD11b-positive/CD14-negative population are considered PMN-MDSC rather than neutrophils. The MDSC of Cruz comprise a mixed immune population derived from bone marrow and were purified by centrifugation and density separation (Materials and Methods sections 2.1-2.2 and Results fir par.).
While the specification and Cruz provide examples of using MDSC to treat COPD, neither give sufficient detail for the one of ordinary skill in the art to predict that all MDSC are capable of treating COPD. The specification provides that MDSC may come from distinct populations and that “heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical significance of these cells.” (par. 27). Bronte notes that gating and filtering strategies cannot distinguish MDSC from their classic myeloid counterparts, neutrophils and monocytes (p. 3). The specification provides cell surface markers by which MDSC may be characterized by flow cytometry, a technique widely available to the ordinary artisan, but offers no guidance on other techniques to identify MDSC suitable for treatment of COPD. Bronte teaches that functional assays are required to distinguish MDSC from non-immunosuppressive immune cells and provides assays to evaluate the functional characteristics of MDSC (p.4 and Tables 2-3). Therefore, there is sufficient guidance in the art for one of ordinary skill in the art to identify a cell source as MDSC and to characterize the immunosuppressive potency of an MDSC population. However, such characterization is not provided in the working example in the specification or in Cruz. Therefore, one of ordinary skill in the art would not be able to predict whether MDSC sourced from a different tissue or isolated by a different method are suitable for treatment of COPD.
Zhang (W. Zhang, et al. J Transl Med, 2021) provides examples of pre-clinical and clinical studies applying MDSC as a cell therapy for the treatment of graft-versus-host disease and various autoimmune diseases, which are inflammatory diseases for the which the immunosuppressive function of MDSC is sought (Tables 1-3). Zhang notes that even when using the MDSC sourced from the same tissue and displaying the same phenotypic markers, some studies show positive results in improving clinical or histological indicators of disease and some do not (Table 3). This indicates that more information about the MDSC and how they are administered is required to predict success in treating inflammatory disease. When applying MDSC to treating COPD, such guidance is not provided in the art or in the specification.
Zhang additionally teaches that induction of functional MDSC is a critical step when applying MDSC as a cell therapy (section 4 p. 9). The specification does not provide a working example of administering MDSC without pre-treatment for COPD. The cells taught by Cruz are not cultured or pre-treated prior to administration. However, the MDSC administered by Cruz were in a mixed population comprising lymphocytes and stem cells. It is unclear without additional guidance whether MDSC can successfully treat COPD when administered alone and without pre-treatment.
Because the specification and the art do not provide guidance to determine whether MDSC are suitable for the treatment of COPD regardless of tissue source, isolation method, or pre-treatment prior to administration, one of ordinary skill in the art would face an undue burden of experimentation when trying to use the invention as claimed.
With regard to co-administration of MDSC with an antibody (claims 5-7 and 9), the specification provides an example wherein mice treated with elastase to model COPD are administered MDSC and/or an antibody against interleukin-10 (IL-10) (Fig. 1). In this model, administration of an anti-IL-10 antibody alone could not reduce inflammation and anti-IL-10 completely reversed the immunosuppressive effect of MDSC. This is a predictable result in view of the prior art. Yaseen (M.M. Yaseen, et al., Open Biol, 2020) teaches that MDSC production of IL-10 is a predominant mechanism behind their immunosuppressive phenotype (section 1, p. 2). Furthermore, IL-10 promotes MDSC expansion in vitro and in vivo, promotes MDSC homing to sites of inflammation, and can push other immune cells toward an MDSC phenotype (Yaseen section 4.1, pp. 4-5). Furthermore, administration of an anti-IL-10 antibody is sufficient to block immunosuppressive action of MDSC in contexts where their action is undesirable, such as in cancer (Yaseen section 6 p. 9). If the specification demonstrates and the state of the art would predict that the invention is not feasible, then one of ordinary skill in the art would face an undue burden of experimentation when trying to use the invention as claimed in claims 6-7 and 9.
With regard to claim 5, Barnes (P.J. Barnes, Nat Rev Immunol, 2018) teaches that several antibodies targeting the inflammatory molecules recited in claim 3, from which claims 5 depends, – interleukin-1, tumor necrosis factor alpha (TNFα), and interleukin-17 – had no effect in treating COPD in clinical trials (Table 1). Together with the example provided in Fig. 1 of the specification, these results show that the observation that an inflammatory marker correlates with disease severity is insufficient to predict that targeting the inflammatory marker will treat the disease. However, the antibodies reported in Barnes were delivered as solo therapies without co-administration with MDSC. However, the specification nor the art provide guidance on how administration of MDSC may overcome lack of efficacy observed in antibody therapies. Furthermore, as demonstrated in the specification, co-administration of MDSC with an anti-IL-10 antibody could not overcome the lack of efficacy of anti-IL-10 administration alone (Fig. 1). Because of lack of predictability in the art, lack of guidance from the art, and lack of guidance from the specification one of ordinary skill in the art would face undue burden of experimentation when trying to use the invention as claimed in claim 5.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. § 103:
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 1-5, 8, 10-14, and 20 are rejected under 35 U.S.C. § 103.
Claims 1-4, 14, and 20 are rejected under 35 U.S.C. § 103 as being unpatentable over Cruz (F.F. Cruz, et al. Resp Phys & Neurobio. 2012) in view of Bronte (V. Bronte, et al. Nat Commun. 2016), Zhang (W. Zhang, et al. J Transl Med, 2021), and Sun (Z. Sun, et al. J Thorac Dis, 2018) and evidenced by Zhang 2020 (W. Zhang, et al. Springer, 2020).
Cruz teaches administration of bone marrow-derived cells comprising 50.1% CD11b-positive/CD14-negative cells for the treatment of chronic obstructive pulmonary disease (COPD) (Abstract, Materials and Methods section 2.1, and Results first par.). The specification teaches that the major population of myeloid derived-suppressor cells (MDSC), polymorphonuclear MDSC (PMN-MDSC), are similar to neutrophils and are CD11b-positive and CD14-negative (par. 27). Therefore, the immunosuppressive cells taught by Cruz comprise CD11b-positive/CD14-negative MDSC. Cruz does not teach administration of fully characterized MDSC, measurement of inflammatory markers pre- and post-treatment, or adjustment of dosing based on post-treatment of inflammatory markers.
Bronte supports that the CD11b-positive/CD14-negative cells of Cruz are MDSC. MDSC are not a distinct cell type identified by a specific path of differentiation, but rather represent a heterogenous population of immature myeloid cells sharing an immunosuppressive phenotype (Bronte p. 2). Gating and filtering strategies cannot distinguish PMN-MDSC from neutrophils (Bronte p. 3). A key difference between neutrophils and PMN-MDSC is that classic activation of neutrophils is characterized by phagocytosis, respiratory burst, and release of pro-inflammatory cytokines that damage tissue, whereas MDSC are potently immunosuppressive and protect tissue from damage in pathological conditions (Bronte p. 5). Given that Cruz observed reduced inflammation in a mouse model of COPD using a mixed immune cell population, the CD11b-positive/CD14-negative population are considered PMN-MDSC rather than neutrophils (claim 1).
Zhang teaches that well-characterized MDSC have been used as cellular therapeutics in numerous pre-clinical and clinical studies for the treatment of transplant rejection and autoimmune diseases based on their immunosuppressive phenotype (claim 1) (Introduction). Zhang additionally teaches that human MDSC are characterized as expressing CD33 (claim 4). Zhang additionally teaches that induction of functional MDSC is a critical step in MDSC-based cell therapy; inducers include prostaglandin E2 (claim 14) and lipopolysaccharide (LPS, a toll-like receptor 4 agonist, claim 20) (section 4).
Regarding steps b) and d) recited in claim 1, Sun teaches monitoring inflammatory markers, such as interleukin-I beta (IL-1β), when administering a cell-based therapy (claims 1-3) (p. 1085). IL-1β is an interleukin-1 family cytokine known to potentiate inflammation via activation of nuclear factor kappa B (NFκB, claims 2-3) (Zhang 2020 pp.1-2). Sun additionally teaches that adjustment of cell therapy parameters, such as dose of cells, dosing approach, and dosing frequency contribute to clinical outcomes (claim 1) (p. 1094). Adjustment of dose and frequency of administration based on pathological parameters is routine practice in therapeutic development.
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 immune cells comprising MDSC taught by Cruz and Bronte with monitoring of pro-inflammatory markers pre- and post-treatment and adjustment of dosing as taught by Sun to arrive at the claimed invention. One would be motivated to make the substitution because using a better characterized cell population of immune cells is important to avoid administering cells that would exacerbate disease as noted by Bronte and because monitoring inflammatory markers and adjusting cell dosing are routine in development of cell therapies for COPD as taught by Sun. One would have a reasonable expectation of success in making the combination because Cruz teaches immune cells as a proof of concept for using MDSC to treat COPD, Zhang teaches that MDSC are commonly used as a cell-based therapy based on their immunosuppressive phenotype, and because monitoring inflammatory markers and adjusting cell dosing are routine in development of cell therapies for COPD as taught by Sun.
Claim 5 is rejected under 35 U.S.C. § 103 as being unpatentable over Cruz, Bronte, Zhang, and Sun as applied to claims 1-4, 14, and 20 above, and further in view of Barnes (P.J. Barnes, Nat Rev Immunol, 2018) and Cayrol (C. Cayrol and J.P. Girard, Cytokine, May 2022).
The use of MDSC to treat COPD, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Cruz, Bronte, Zhang, and Sun as discussed in the rejections of claims 1-4, 14, and 20 above. The references do not teach co-administration of MDSC with an antibody targeting one of the inflammatory molecules recited in claim 3 as required by claim 5.
Cayrol teaches that antibody therapy targeting interleukin-33 (IL-33) has been clinically evaluated for COPD with efficacy in former smokers (claim 5) (p. 12). Each element of claim 5 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.
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 treating COPD with MDSC, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Cruz, Bronte, Zhang, and Sun with an antibody therapy targeting an inflammatory marker as taught by Barnes to arrive at the claimed invention. One would be motivated to make such a combination because the clinical efficacy of MDSC for COPD has not been tested, but antibody therapy against IL-33 has demonstrated efficacy, improving the likelihood of success by combining multiple modes of therapy. One would have a reasonable expectation of success in making the combination as both MDSC and anti-IL-33 antibodies have been evaluated in vivo and can be expected to be more effective in combination.
Claims 8, 10-11, and 13 are rejected under 35 U.S.C. § 103 as being unpatentable over Cruz, Bronte, Zhang, and Sun as applied to claims 1-4, 14, and 20 above, and further in view of Yaseen (M.M. Yaseen, et al., Open Biol, 2020) and Casacuberta‐Serra (S. Casacuberta‐Serra, et al., Immunol Cell Biol, 2017).
The use of MDSC to treat COPD, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Cruz, Bronte, Zhang, and Sun as discussed in the rejections of claims 1-4, 14, and 20 above. Zhang additionally teaches that induction of functional MDSC is a critical step in MDSC-based cell therapy (p. 9). The references do not teach culturing myeloid cells in the presence of interleukin-10 (IL-10) as required by claims 8 and 11, interleukin-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) as required by claims 10-11, or transforming growth factor beta (TGFβ) as required by claim 13.
However, Yaseen teaches that treatment with IL-10 enhances MDSC proliferation in vitro (i.e., cell culture, claims 8 and 11) (sec 4.1, p. 5). Yaseen additionally teaches that MDSC produce IL-10 and that a positive feedback loop promotes MDSC expansion and immunosuppressive phenotype (sec 4.1, p. 5).
Furthermore, Casacuberta-Serra teaches in vitro generation of monocytic MDSC (M-MDSC) from monocytes by culturing with GM-CSF and TGFβ1, a species of TGFβ (claim 13) (Fig. 1). Casacuberta-Serra additionally teaches in vitro generation of granulocytic MDSC (G-MDSC, also referred to as PMN-MDSC) and M-MDSC from hematopoietic progenitor cells by culturing with GM-CSF and IL-3 (claims 10-11) (Fig. 1).
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 treating COPD with MDSC, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Cruz, Bronte, Zhang, and Sun with priming MDSC with combinations of IL-10, IL-3, GM-CSF, and TGFβ as taught by Zhang, Yaseen, and Casacuberta-Serra to arrive at the claimed invention. One would be motivated to make such a combination because Zhang teaches that priming MDSC prior to use in cell therapy is a critical step, Yaseen teaches that IL-10 enhances in vitro expansion of MDSC and immunosuppressive phenotype, and Casacuberta-Serra teaches established combinations of stimulatory molecules for generating MDSC. One would have a reasonable expectation of success in making the combination as MDSC are taught as cell therapies based on their immunosuppressive phenotype, IL-10 improves MDSC immunosuppressive function, and IL-10, IL-3, GM-CSF, and TGFβ are established stimulatory molecules for generating MDSC.
Claim 12 is rejected under 35 U.S.C. § 103 as being unpatentable over Cruz, Bronte, Zhang, and Sun as applied to claims 1-4, 14, and 20 above, and further in view of Corzo (C.A. Corzo, et al., J Exp Med, 2010).
The use of MDSC to treat COPD, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Cruz, Bronte, Zhang, and Sun as discussed in the rejections of claims 1-4, 14, and 20 above. Zhang additionally teaches that induction of functional MDSC is a critical step in MDSC-based cell therapy (p. 9). The references do not teach culturing myeloid cells in hypoxic conditions as required by claim 12.
However, Corzo teaches that treatment of MDSC with hypoxia in vitro (i.e., in cell culture, claim 12) enhanced their immunosuppressive function (Fig. 5 and p. 2445).
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 treating COPD with MDSC, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Cruz, Bronte, Zhang, and Sun with priming MDSC with hypoxia as taught by Zhang and Corzo to arrive at the claimed invention. One would be motivated to make such a combination because Zhang teaches that priming MDSC prior to use in cell therapy is a critical step and Corzo teaches that hypoxia improves the immunosuppressive function of MDSC. One would have a reasonable expectation of success in making the combination as MDSC are taught as cell therapies based on their immunosuppressive phenotype and hypoxia improves MDSC immunosuppressive function.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines which form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 8, 10-14, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/316,084. Although the conflicting claims are not identical, they are not patentably distinct because the instant claims are obvious variants of the copending application claim. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 14, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/316,084 in view of Sun (Z. Sun, et al. J Thorac Dis, 2018) and Zhang (W. Zhang, et al. J Transl Med, 2021) and as evidenced by Zhang 2020 (W. Zhang, et al. Springer, 2020).
Claim 9 of Application No. 18/316,084 is drawn to a method of treating chronic obstructive pulmonary disease (COPD) comprising administration of 1) myeloid derived suppressor cells (MDSC) and/or a compound that promotes proliferation or enhanced activity of MDSC and 2) mesenchymal stem cells (MSC). Claim 9 of Application No. 18/316,084 is not drawn to administration of MDSC alone and does not require adjustment of dosing based on a patient’s pre- and post-treatment inflammatory marker levels or pathological state.
Sun teaches that treatment of COPD by administration of MSC is an active area of development because the reparative effects of MSC are attributed, in part, to their immunosuppressive phenotype (Abstract and p. 1087). Regarding steps b) and d) recited in claim 1, Sun teaches monitoring inflammatory markers, such as interleukin-I beta (IL-1β), when administering a cell-based therapy (claims 1-3) (p. 1085). IL-1β is an interleukin-1 family cytokine known to potentiate inflammation via activation of nuclear factor kappa B (NFκB, claims 2-3) (Zhang 2020 pp.1-2). Sun additionally teaches that adjustment of cell therapy parameters, such as dose of cells, dosing approach, and dosing frequency contribute to clinical outcomes (claim 1) (p. 1094). Adjustment of dose and frequency of administration based on pathological parameters is routine practice in therapeutic development.
Zhang teaches that MDSC have been used as cellular therapeutics in numerous pre-clinical and clinical studies for the treatment of transplant rejection and autoimmune diseases based on their immunosuppressive phenotype (claim 1) (Introduction). Zhang additionally teaches that human MDSC are characterized as expressing CD33 (claim 4). Zhang additionally teaches that induction of functional MDSC is a critical step in MDSC-based cell therapy; inducers include prostaglandin E2 (claim 14) and lipopolysaccharide (LPS, a toll-like receptor 4 agonist, claim 20) (section 4).
Therefore, it would have been obvious to one of ordinary skill in the art to try administration of MDSC as a standalone therapy for the treatment of COPD and to combine the method with monitoring of pro-inflammatory markers pre- and post-treatment and adjustment of dosing as taught by Sun and Zhang to arrive at the claimed invention. One would be motivated to try MDSC as a standalone therapy for treating COPD because administration of a cell therapy is sought for treatment of COPD to reduce inflammation as taught by Sun and because MDSC also have an immunosuppressive phenotype as taught by Zhang. One would have a reasonable expectation of success in trying MDSC as a standalone therapy for COPD because Zhang teaches that MDSC are immunosuppressive, which is the characteristic taught by Sun as the mode by which MSC are used for treating COPD.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/316,084 in view of Sun and Zhang above, and further in view of Barnes (P.J. Barnes, Nat Rev Immunol, 2018) and Cayrol (C. Cayrol and J.P. Girard, Cytokine, May 2022).
The use of MDSC to treat COPD, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Sun and Zhang as discussed in the rejections of claims 1-4, 14, and 20 above. Claim 9 of Application No. 18/316,084 does not require, and the references do not teach, co-administration of MDSC with an antibody targeting one of the inflammatory molecules recited in claim 3 as required by claim 5.
Cayrol teaches that antibody therapy targeting interleukin-33 (IL-33) has been clinically evaluated for COPD with efficacy in former smokers (claim 5) (p. 12). Each element of claim 5 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.
Therefore, it would have been obvious to one of ordinary skill in the art to combine the method of treating COPD with MDSC, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Sun and Zhang with an antibody therapy targeting an inflammatory marker as taught by Barnes to arrive at the claimed invention. One would be motivated to make such a combination because the clinical efficacy of MDSC for COPD has not been tested, but antibody therapy against IL-33 has demonstrated efficacy, improving the likelihood of success by combining multiple modes of therapy. One would have a reasonable expectation of success in making the combination as both MDSC and anti-IL-33 antibodies have been evaluated in vivo and can be expected to be more effective in combination.
Claims 8, 10-11, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/316,084 in view of Sun and Zhang above, and further in view of Yaseen (M.M. Yaseen, et al., Open Biol, 2020) and Casacuberta‐Serra (S. Casacuberta‐Serra, et al., Immunol Cell Biol, 2017).
The use of MDSC to treat COPD, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Sun and Zhang as discussed in the rejections of claims 1-4, 14, and 20 above. Zhang additionally teaches that induction of functional MDSC is a critical step in MDSC-based cell therapy (p. 9). Claim 9 of Application No. 18/316,084 and the references do not teach culturing myeloid cells in the presence of interleukin-10 (IL-10) as required by claims 8 and 11, interleukin-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) as required by claims 10-11, or transforming growth factor beta (TGFβ) as required by claim 13.
However, Yaseen teaches that treatment with IL-10 enhances MDSC proliferation in vitro (i.e., cell culture, claims 8 and 11) (sec 4.1, p. 5). Yaseen additionally teaches that MDSC produce IL-10 and that a positive feedback loop promotes MDSC expansion and immunosuppressive phenotype (sec 4.1, p. 5).
Furthermore, Casacuberta-Serra teaches in vitro generation of monocytic MDSC (M-MDSC) from monocytes by culturing with GM-CSF and TGFβ1, a species of TGFβ (claim 13) (Fig. 1). Casacuberta-Serra additionally teaches in vitro generation of granulocytic MDSC (G-MDSC, also referred to as PMN-MDSC) and M-MDSC from hematopoietic progenitor cells by culturing with GM-CSF and IL-3 (claims 10-11) (Fig. 1).
Therefore, it would have been obvious to one of ordinary skill in the art to combine the method of treating COPD with MDSC, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Sun and Zhang with priming MDSC with combinations of IL-10, IL-3, GM-CSF, and TGFβ as taught by Zhang, Yaseen, and Casacuberta-Serra to arrive at the claimed invention. One would be motivated to make such a combination because Zhang teaches that priming MDSC prior to use in cell therapy is a critical step, Yaseen teaches that IL-10 enhances in vitro expansion of MDSC and immunosuppressive phenotype, and Casacuberta-Serra teaches established combinations of stimulatory molecules for generating MDSC. One would have a reasonable expectation of success in making the combination as MDSC are taught as cell therapies based on their immunosuppressive phenotype, IL-10 improves MDSC immunosuppressive function, and IL-10, IL-3, GM-CSF, and TGFβ are established stimulatory molecules for generating MDSC.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/316,084 in view of Sun and Zhang above, and further in view of Corzo (C.A. Corzo, et al., J Exp Med, 2010).
The use of MDSC to treat COPD, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Sun and Zhang as discussed in the rejections of claims 1-4, 14, and 20 above. Zhang additionally teaches that induction of functional MDSC is a critical step in MDSC-based cell therapy (p. 9). Claim 9 of Application No. 18/316,084 does not require, and the references do not teach, culturing myeloid cells in hypoxic conditions as required by claim 12.
However, Corzo teaches that treatment of MDSC with hypoxia in vitro (i.e., in cell culture, claim 12) enhanced their immunosuppressive function (Fig. 5 and p. 2445).
Therefore, it would have been obvious to one of ordinary skill in the art to combine the method of treating COPD with MDSC, monitoring of pre- and post-treatment inflammatory markers, and adjustment of dosing are taught by Sun and Zhang with priming MDSC with hypoxia as taught by Zhang and Corzo to arrive at the claimed invention. One would be motivated to make such a combination because Zhang teaches that priming MDSC prior to use in cell therapy is a critical step and Corzo teaches that hypoxia improves the immunosuppressive function of MDSC. One would have a reasonable expectation of success in making the combination as MDSC are taught as cell therapies based on their immunosuppressive phenotype and hypoxia improves MDSC immunosuppressive function.
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