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 .
DETAILED ACTION
The instant application is in response to the papers filed on June 21, 2023 of which claims 1-12 were filed, and are currently pending. Therefore, claims 1-12 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application claims foreign priority 35 U.S.C. 119(a)-(d) to People’s Republic of China Patent Application No. 202210721593.5 filed on June 24, 2022.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Thus, the earliest possible priority for the instant application is June 24, 2022.
Drawings
The drawings are objected to because FIG 5A-D appear to depict the significance with the labels “&” and “#”, yet this is not standard practice, and additionally, there is no corresponding information in the Specification to provide insight on how to interpret these results. The standard practice is to use “*”, “**”, and “***” dependent on the level of significance represented.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1 and 11 are objected to because of the following informalities: The claims recite, “a preparation method of the PGE2-primed MSC product comprises conducting mixed culture on PGE2 and MSCs to obtain the PGE2-primed MSC product.” It is unclear how mixed culture is conducted on PGE2 and MSCs, as it appears the Applicant intended to use “with” as opposed to “on”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected for being indefinite as it is not clear as to what the scope of the claim is directed to as it recites both a method of preparation and a method of treatment in a single claim. Moreover, the claim recites a preamble “A method for treating lung injury (LI),” and then is directly followed by a “wherein” clause as opposes to a standard transitional phrase then the body of the claim as described in MPEP 2111.02-2111.04; “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are: …(B) "wherein" clauses; …The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps").” (MPEP 2111.04).
In the instant case, it is unclear if the claim is directed to the method steps of treatment or rather the method steps of preparation. If claim 1 is directed to a method of treatment, the claim should not recite “wherein” followed by the active steps necessary for the method of treatment, and moreover, the steps pertaining to preparation should be followed by a wherein clause to further clarify the claim scope as being directed to treatment. Additionally, if claim 1 is directed to a method of preparation, then the preamble should state this method followed by the relevant active steps, e.g. “A preparation method of a PGE2-primed MSC product comprises conducting a mixed culture on PGE2 and MSCs to obtain the PGE2-primed MSC product, wherein…”. Altogether, the claim is indefinite because the scope is unclear since it is directed to two different methods, and secondly for the structure of the claim not being proper, i.e. preamble, transitional phrase, and body.
Claim 11 is similarly rejected as it directed to two statutory categories, i.e. a composition and a method of preparation. It appears the claim is intended to be directed to a product based on the preamble, and the recitation of “and a preparation method of the PGE2-primed MSC product comprises conducting mixed culture on PGE2 and MSCs to obtain the PGE2-primed MSC product.” should be proceeded by a wherein clause. MPEP 2173.05 (p) states, “A product-by-process claim, which is a product claim that defines the claimed product in terms of the process by which it is made, is proper. … A claim to a device, apparatus, manufacture, or composition of matter may contain a reference to the process in which it is intended to be used without being objectionable under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, so long as it is clear that the claim is directed to the product and not the process.” In the instant case, as the claim is currently written, it is unclear that the claim is directed to the product and not the process of making, and therefore is considered indefinite under 35 U.S.C. 112(b).
Claim 1 is indefinite as it is unclear if the prostaglandin E2 (PGE2)-primed mesenchymal stem cell (MSC) drug and the PGE2-primed MSC product recited in the same claim are the same compositions or rather different compositions, and moreover, what the necessary steps are to derive the prostaglandin E2 (PGE2)-primed mesenchymal stem cell (MSC) drug from the PGE2-primed MSC product, and how these compositions are different. Claim 11 provides clarity that the drug comprises the derived product, however, this is unclear for the scope set forth in claim 1 wherein these limitations are not present and because claim 11 is not dependent on claim 1.
Claim 5 is indefinite in the recitation of “the mixed culture is based on Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F12)” because it is unclear if the use of “based on” is intended to mean “comprises”, “consists essentially of”, or “consists”, or rather is representative of DMEM in terms of compounds but not concentrations or more specifically compounds and corresponding concentration ratios. The Specification employs the same language, but the claim scope remains unclear in view of this language. In summary, the use of “based on” is indefinite, and it is preferable to use the standard transitional phrases to clarify the scope of the claim.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7-12 are rejected under 35 U.S.C. 103 as being unpatentable over Shoemaker et al. (US-9,452,186-B2) in view of Harrell et al. (Analytical cellular pathology 2020.1 (2020): 1939768) and Noronha et al. (Stem cell research & therapy 10.1 (2019): 131).
Regarding claim 1, directed to a method of treatment and a method of preparation/making, and claim 11 directed to a drug and the same method of preparation/making as recited in claim 1, Shoemaker teaches enhanced stem cells that have improved homing and engraftment properties and the corresponding methods of making and treatments with these enhanced cells (abstract). Shoemaker teaches stem cells that are contacted with ex vivo with prostaglandin agonists, particularly PGE2 within culture medium (col 2, ln 60-col 3, ln 8; col 36, ln 17-26). Moreover, Shoemaker teaches using the treated stem cells to treat lung injuries as seen in treating non-hematological cancers such as solid tumors (including lung cancer) then further stating tissues that are suitable for treatment with the compositions include lung tissues, and lastly describing it is “suitable for treatment or amelioration using the methods of the present invention, include, but are not limited to, acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS)” (col 40, ln 1-5; col 44, ln 35-58).
In reference to the “priming” limitation, Shoemaker teaches this limitation based on the claimed contacting step being similar to what is taught by Shoemaker, and furthermore describing that, “By “enhance” or “promote,” or “increase” or “activate” refers generally to the ability of an agent to produce or cause a greater physiological response (i.e., downstream effects) in a cell, as compared to the response caused by either vehicle or a control molecule/composition, e.g., increased engraftment/engraftment potential of hematopoietic stem and progenitor cells and increased in vivo stem cell expansion. A measurable physiological response may include an increase in hematopoietic stem and progenitor cell engraftment, viability, homing, self-renewal, and/or expansion, among others apparent from the understanding in the art and the description herein.” (col 22, ln 27-37).
Shoemaker does not teach mesenchymal stem cells that are primed, and but rather primed/activated hematopoietic stem cells (HSCs) or hematopoietic progenitor cells (HPCs) stating, “Hematopoietic stem cells are multipotent stem cells that give rise to all the blood cell types of an organism, including myeloid (e.g., monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (e.g., T-cells, B-cells, NK-cells), … Hematopoietic progenitor cells (HSCs) give rise to committed hematopoietic progenitor cells (HPCs) that are capable of generating the entire repertoire of mature blood cells over the lifetime of an organism.” (col 24, 28-42). Moreover, Shoemaker does not teach using the primed MSCs for treating lung injury.
Harrell teaches mesenchymal stem cells can be used in the treatment of inflammatory and degenerative diseases, specifically acute respiratory distress syndrome (ARDS). In particular, Harrell describes the evidence from the studies and trials with using MSC for ARDS, “MSCs enhanced regeneration of AT2 and endothelial cells, alleviated inflammation, reduced pulmonary edema, improved oxygenation, and prolonged survival of mice suffering from ARDS [18]. Beneficial effects of MSCs were due to the enhanced immunosuppression and improved oxygenation in the injured lungs [18]. MSC-based inhibition of detrimental immune response in the lungs mainly relied on the anti-inflammatory effects of MSC-sourced PGE2 and IL-10 [16, 24]. MSC-derived PGE2 induced generation of the immunosuppressive M2 phenotype in alveolar macrophages and increased their capacity for IL-10 production [26]. IL-10, released by MSCs and M2 macro-phages, attenuated secretion of inflammatory TNF-α in lung-infiltrated lymphocytes and inhibited production of ROS and other inflammatory mediators in neutrophils and monocytes”; and that “MSCs was a safe therapeutic approach for the treatment of patients with moderate and severe ARDS” based on a clinical trial. (p 4 Sec. 3).
Shoemaker and Harrell do not teach the priming of MSC.
Noronha teaches MSC have been investigated in cell-based therapies for their anti-inflammatory, immunosuppressive, immunomodulatory, and regenerative properties, and several molecules produced by MSC are able to influence (suppress or modulate) the immune responses, such as PGE2 (p 1, col 2- p 2, col 1). The review then describes that several priming approaches have been proposed to improve MSC function, survival, and therapeutic efficacy using different types of stimuli (Tables 1-4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition and methods pertaining to making and using as taught by Shoemaker because it would have been obvious to substitute one known element for another to obtain predictable results. Substituting the claimed MSC as taught by Harrell and Noronha for the HSC in the composition of Shoemaker would have led to predictable results with a reasonable expectation of success because Harrell teaches MSCs are used in the treatment of lung injuries, and moreover the lipid mediator PGE2 functions in the resulting anti-inflammatory phenotype, and Noronha describing an extensive literature wherein MSCs are primed with various agents to provide therapeutic effects based on their anti-inflammatory, immunosuppressive, immunomodulatory, and regenerative properties. Therefore, there is a reasonable expectation that primed MSCs with PGE2 would be have a predictable outcome of treating lung injuries.
Regarding claims 2 and 12, Shoemaker teaches the time period for treatment with PGE2 occurs from 12 – 24 hours (col 37, ln 3-16).
Regarding claims 3 and 4, the rejection to claim 1 makes obvious that Shoemaker in view of Harrell and Noronha teach wherein the PGE2-primed MSC product comprises PGE2-primed MSCs.
Regarding claims 7 and 8, Noronha teaches MSC that are primed, wherein the MSC is one or more selected from the group consisting of placental-derived mesenchymal stem cell (PMSC), bone marrow mesenchymal stem cell (BMMSC), adipose mesenchymal stem cell (AMSC), umbilical cord mesenchymal stem cell (UCMSC), and endothelial progenitor cell (EPC), (Tables 1-4).
Regarding claims 9 and 10, the rejection to claim 1 makes obvious that Shoemaker in view of Harrell and Noronha teach wherein the LI is one or more selected from the group consisting of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary fibrosis, silicosis, and radiation-induced LI )” (col 40, ln 1-5; col 44, ln 35-58). Moreover, Harrell teaches using MSC for treating ARDS (abstract).
Claims 1-2, and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Shoemaker et al. (US-9,452,186-B2) in view of Harrell et al. (Analytical cellular pathology 2020.1 (2020): 1939768) and Noronha et al. (Stem cell research & therapy 10.1 (2019): 131) as applied to claims 1-2, and further in view of Giuliani et al. (Blood, The Journal of the American Society of Hematology 118.12 (2011): 3254-3262).
Regarding claims 1 and 2, the disclosure of Shoemaker in view of Harrell and Noronha is applied as in the 103 rejections above, the content of which is incorporated above, in its entirety.
Regarding claims 5 and 6, Shoemaker teaches using serum-free medium that comprises “basal medium IMDM plus 2 mM L-glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin,”(Col 53).
Shoemaker in view of Harrell and Noronha do not teach wherein a culture medium for the mixed culture is based on Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/Fl2) and further
supplemented with components of the following concentrations: 100 mL/L fetal bovine serum
(FBS), 10 g/L L-glutamine, 10 mL/L non-essential amino acid solution, and 10 mL/L penicillin -streptomycin mixture.
Giuliani teaches culturing MSC in DMEM/F12 medium, supplemented with 10% FBS, 0.1mM nonessential amino acids, 1mM L-glutamine, and 1 x penicillin-streptomycin. The cells were cultured for 4 weeks then characterized via flow cytometry to certify expression of pluripotency markers Oct4, Sox2, Nanog, and Lin28.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have employed the culture medium for MSC as taught by Guiliani because it would have been obvious to substitute one known element for another to obtain predictable results. Substituting the claimed culture medium elements as taught by Guiliani for the culture medium composition of Shoemaker would have led to predictable results with a reasonable expectation of success because Guiliani teaches successful outcomes of using these claimed culture medium for the isolation and expansion of MSCs. Moreover, it would be obvious to optimize the culture medium elements concentrations in order to obtain healthy MSCs in the highest concentration to be used in downstream therapeutic applications.
Conclusion
Claims 1-12 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/ Examiner, Art Unit 1634
/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634