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
This action is in response to papers filed June 27, 2026. Pursuant to the amendments filed June 26, 2026, claims 1-3, 7, 10-12, 16-21, and 25-33 are currently pending. Claims 1-2, 7, 10, have been amended, claims 7 and 10 have been withdrawn, claims 32-33 are newly added and claim 6 has been canceled by Applicants’ amendment filed on 6/27/2026.
Applicants’ election of Group I (e.g. claims 1-3, 11-12, 16-21 and 25-31) with traverse, is acknowledged. Further, Applicants’ species election required of claims 1-3, 16-17, 19-21, 26, 28 and newly added claim 33, as recited in the Response to Election/Restriction filed June 27, 2026, without traverse has been acknowledged.
Claims 7 and 10 have been withdrawn from consideration by Applicants pursuant to the Restriction filed 4/29/2026 in Applicants’ amendment filed on 6/27/2026. In view of Applicants amendments and upon further considerations, claims 7 and 10 are considered to the elected invention and are rejoined for examination. The restriction requirement is deemed proper and made FINAL.
Therefore, claims 1-3, 7, 10-12, 16-21 and 25-33 are under examination to which the following grounds of rejection are applicable. Claim 32 is an independent claim.
Priority
The instant application claims priority to International Application PCT/US2022/074305, filed on July 29, 2022. The International Application claims priority to US Provisional Application 63/227,009 filed July 29, 2021.
Therefore, the earliest effective filing date for the instant application is July 29, 2021.
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.
Claim 1-3, 7, 10-12, 16-21 and 25-33 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 32 in indefinite in its recitation of “at least in part”. The term " in part " is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required.
Claim 32 is indefinite because of the recitation of the terms “measuring” and “classifying”. These are terms that require a reference control. It is unclear in reference to what the indicators of a response of the MSCs and the therapeutic efficacy of the MSCs based on the measuring are relative to.
Claim 32 recites a plurality of the term “and/or” . For example, it is unclear what the metes and bounds of this term, as “and” could be interpreted to include only proteins, or all of the proteins, phospho-proteins and genes in the MAPK pathway , or, “or” would imply that the same proteins, phospho-proteins and genes in the MAPK pathway are in the alternative. Appropriate correction is requested.
Claims 33 recites “standard control” The term "standard" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required.
Claim 33 recites the term “greater secretion” .The recitation of term “greater secretion” is a relative term and renders the claim indefinite. The term " secretion " is not defined by the claim. What amount conditions are considered "greater" varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 33 recites a plurality of the term “substantially” . Claim 33 is indefinite in its recitation of the phrase “substantially similar” since it is unclear how this term “substantially” is defined, what its metes and bounds are, or to what the term is directed towards. It is not clear in reference to what extent the similarity of the secretion and levels of proteins are completed.
Claim 33 recites the term “greater secretion” .The recitation of term “greater secretion” is a relative term and renders the claim indefinite. The term " secretion " is not defined by the claim. What amount conditions are considered "greater" varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 1 recites a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed protein cannot be simultaneously be each of the structurally different molecules recited. To put it another way, the protein cannot be both a chemokine and not a chemokine. Appropriate correction is required.
Claim 1 recites the term “greater secretion” and “lower secretion” .The recitation of term “greater secretion” or “lower secretion” is a relative term and renders the claim indefinite. The term " secretion " is not defined by the claim. What amount conditions are considered "greater" or “lower” varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 1 is indefinite because of the recitation of the terms “measuring” and “classifying”. These are terms that require a reference control. It is unclear in reference to what the indicators of a response of the MSCs and the therapeutic efficacy of the MSCs based on the measuring are relative to.
Claim 1 recites a plurality of the term “substantially” . Claim 33 is indefinite in its recitation of the phrase “substantially similar” since it is unclear how this term “substantially” is defined, what its metes and bounds are, or to what the term is directed towards. It is not clear in reference to what extent the similarity of the secretion and levels of proteins are completed.
Claims 1 , recite “standard control” The term "standard" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required.
Claim 2 recites “highly therapeutic” , “less therapeutic”. The recitation of term “highly therapeutic” or “less therapeutic” is a relative term and renders the claim indefinite. The term " therapeutic MSCs " is not defined by the claim. What amount conditions are considered "highly " or “less” varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 2 recites a plurality of “more able to”. Claim 2 is vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Claim 2 is indefinite in its recitation of “decrease fibrillation development”, “reduce development”, “decrease proteoglycan loss”, “decrease subchondral bone sclerosis”, “decrease synovitis”, “decrease proteoglycan loss”, “decrease subchondral bone sclerosis”, “decrease synovitis”, “decrease pain”, “decrease loss of function of a joint”. These are relative term and renders the claim indefinite.
Claim 2 recites a plurality of “ MSCs are MSCs likely”. As written, claim 2 appears to provide examples and preferences for MSCs. It is not clear, however, whether other types of MSCs or which particular forms of MSCs are intended to be within the scope of the claim. Accordingly, claim 2 is indefinite because its metes and bounds are unclear.
Claim 3 recites a plurality of the term “and/or”. For example, it is unclear what the metes and bounds of this term, as “and” could be interpreted to include only proteins, or all of the proteins, phospho-proteins and genes in the MAPK pathway , or, “or” would imply that the same proteins, phospho-proteins and genes in the MAPK pathway are in the alternative. Appropriate correction is requested.
Claim 7 is indefinite in its recitation of “the classifying comprises classifying the MSCs as being therapeutically effective”. These are terms that require a reference control. It is unclear in reference to what the classifying the MSCs as being therapeutically effective for treating osteoarthritis in a subject in need thereof is relative to.
Claim 7 recites a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed protein cannot be simultaneously be each of the structurally different molecules recited. To put it another way, the protein cannot be both a chemokine and not a chemokine. Appropriate correction is required.
Regarding claim 10, it in definite in its recitation of the term “therapeutic MSCs” as there is insufficient antecedent basis for this limitation in the claim. Claim 7 only recites (the MSCs).
Claim 11 is indefinite in its recitation of “highly therapeutic” , “less therapeutic”. The recitation of term “highly therapeutic” or “less therapeutic” is a relative term and renders the claim indefinite. The term " therapeutic MSCs " is not defined by the claim. What amount conditions are considered "highly " or “less” varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 11 recites a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed protein cannot be simultaneously be each of the structurally different molecules recited. To put it another way, the protein cannot be both a chemokine and not a chemokine. Appropriate correction is required.
Claim 12 recites a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed protein cannot be simultaneously be each of the structurally different molecules recited. To put it another way, the protein cannot be both a chemokine and not a chemokine. Appropriate correction is required.
Claim 12 is indefinite in its recitation of “highly therapeutic” , “less therapeutic”. The recitation of term “highly therapeutic” or “less therapeutic” is a relative term and renders the claim indefinite. The term " therapeutic MSCs " is not defined by the claim. What amount conditions are considered "highly " or “less” varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 17 recites is in improper Markush form; a Markush group should be in the form “the JNK activator selected from the group consisting of A, B, and C”. Thus, given this ambiguity, one skilled in the art cannot reasonably determine the metes and bounds of the claimed invention due to an inability to envision all members of the Markush group.
Claim 17 recites is in improper Markush form; a Markush group should be in the form “the JNK activator selected from the group consisting of A, B, and C”. Thus, given this ambiguity, one skilled in the art cannot reasonably determine the metes and bounds of the claimed invention due to an inability to envision all members of the Markush group.
Claim 19 recites is in improper Markush form; a Markush group should be in the form “the p-Akt inhibitor selected from the group consisting of A, B, and C”. Thus, given this ambiguity, one skilled in the art cannot reasonably determine the metes and bounds of the claimed invention due to an inability to envision all members of the Markush group.
Regarding claim 20, it is indefinite in its recitation of the term “the subject” as there is insufficient antecedent basis for the limitation of the claim.
Claim 20 recites a plurality of “and/or” conjunctions. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed protein cannot be simultaneously be each of the structurally different molecules recited. For example, it is unclear what the metes and bounds of this term, as “and” could be interpreted to include only activators and inhibitors in the MAPK pathway , or, all the activators and inhibitors “or” would imply that the activators and inhibitors in the MAPK pathway are in the alternative.
Claim 21 recites “highly therapeutic” , “less therapeutic”. The recitation of term “highly therapeutic” or “less therapeutic” is a relative term and renders the claim indefinite. The term " therapeutic MSCs " is not defined by the claim. What amount conditions are considered "highly " or “less” varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 20 recites a plurality of “and/or” conjunctions that renders the claim indefinite.
Claim 26 recites is in improper Markush form; a Markush group should be in the form “the JNK activator selected from the group consisting of A, B, and C”. Thus, given this ambiguity, one skilled in the art cannot reasonably determine the metes and bounds of the claimed invention due to an inability to envision all members of the Markush group.
Claim 27 is indefinite for because a broad range or limitation is together with a narrow range of limitation that falls within the broad range or limitation (in the same claim) is considered indefinite since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. In the instant case the claim recites the broad limitation “inhibitor of the PBK/Akt pathway” and the claim recites “a phosphorylated Akt (p-Akt) inhibitor” which is a narrower statement of said limitation.
Claim 28 recites is in improper Markush form; a Markush group should be in the form “the p-Akt inhibitor selected from the group consisting of A, B, and C”. Thus, given this ambiguity, one skilled in the art cannot reasonably determine the metes and bounds of the claimed invention due to an inability to envision all members of the Markush group.
Regarding claim 29, it is indefinite in its recitation of the term “the MSCs” as there is insufficient antecedent basis. Claim 20 recites “the highly therapeutic MSCs”.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 7, 10-12, 16-21 and 25-33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception, specifically the mental process of measuring and classifying mesenchymal stem cells as highly therapeutic, without significantly more. Claim 32 recites incubating the mesenchymal stromal cells (MSCs) with cytokines, measuring the level of indicators secreted, then classifying the therapeutic efficacy of the MSCs based on the measuring. MPEP § 2106 sets forth the multi-step process for determining subject matter eligibility.
In accordance with the MPEP § 210 6, claimed found to recite a statutory subject matter (e.g., a calculation process comprising a incubating step, measuring steps and classifying step) (Step 1: YES) are the analyzed to determine if the claims recite any steps that equate to an abstract idea, law of nature, or natural phenomenon. MPEP § 2106 (a)(2) subsection III recites “The courts consider a mental process (thinking) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all.’" 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work’" (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same)”. Independent claim 32 recites “measuring at least one indicator” step and “classifying a therapeutic efficacy of the MSCs” step because it recites evaluating the measured response of MSCs and classifying the therapeutic efficacy of the MSCs based upon that measurement, which can be performed in the human mind. The step of classifying merely analyzes the measured information and reaches a conclusion regarding therapeutic efficacy without requiring any particular technological implementation or transformation. (Step 2A, Prong One: YES)
Step 2A Prong Two: the additional element of the “incubating mesenchymal stromal cells (MSCs) with one or more cytokines” step is recited at such a high level of generality that it is at best mere instructions to apply the exception. (no integration into a practical application). As taught by Chang et al. ( Published: 2019. US Publication: US 20190160105 A1). Chang teaches a method of selecting high efficacy stem cells based on the expression of vascular endothelial growth factor for treating cerebrovascular disease (para 0007, “Thus, the present disclosure provides a method for selecting a high efficacy stem cell for treating a cerebrovascular disease, the method including a step of measuring a level of a VEGF and a high efficacy stem cell selected by the method.”; Claim 1, “A method for selecting a high efficacy stem cell for treating a cerebrovascular disease, the method comprising: measuring an expression level of a vascular endothelial growth factor (VEGF).”; Claim 2, “The method according to claim 1, wherein the method comprises: (a) culturing stem cells; (b) measuring a concentration of a VEGF in a culture solution of the stem cells in Step (a); and (c) evaluating an ability to protect nerve cells based on the measured concentration.”; Claim 3, “The method according to claim 3, wherein the evaluation of the ability to protect nerve cells is determined to be high efficacy when the measured concentration of the VEGF is 100 pg/ml or more.”).
The step of incubating MSCs with one or more cytokines merely prepares the cells for observation, while the step of measuring and the step of classifying relies on gathering information regarding the cellular response. Moreover, the claims merely rely on the determination of therapeutic efficacy.
The judicial exception is not integrated into a practical application because they do not recite any elements in addition to the recited judicial exception. MPEP 2106.04(d), subsection III states that a judicial exception alone is not eligible subject matter; therefore, if there are no additional claim elements besides the judicial, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application.
Step 2B The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. MPEP 2106.05, subsection I states that additional elements in the claims must be evaluated to determine whether they amount to an inventive concept, which requires considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself. (Step 2B: NO).,
Therefore, claims 32 is patent ineligible. Furthermore claims 1-3, 7, 10-12, 16-21 and 25-31 and 33 are rejected 35 U.S.C. § 101 because they do not further integrate claim 1 into a practical application. Thus claims 1-3, 7, 10-12, 16-21 and 25-31 and 33 are not patent eligible.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3, and 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Redondo-Castro (Published: 2017. Stem cell research & therapy, 8(1), 79. Cited in ISR filed 1/26/2024), in further view of Chang et al. ( Published: 2019. US Publication: US 20190160105 A1).
Regarding claim 32, Redondo-Castro teaches a method comprising the step of culturing mesenchymal stem cells (MSCs) in vitro interleukin 1 beta (IL-1), tumor necrosis factor (TNF-a) and interferon gamma (INFy) (pp. 1, Abstract, “Human MSCs from three different donors were cultured in vitro and treated with inflammatory mediators as follows: interleukin (IL)-1α, IL-1β, tumour necrosis factor alpha (TNF-α) or interferon-γ.”). Moreover, Redondo-Castro teaches measuring one indicator of a response to culturing the MSCs in these inflammatory cytokines by measuring TNF-a, IL-10, G-CSF and IL-6 expression measured by an ELISA (pp. 1, Abstract, “To confirm the anti-inflammatory potential of MSCs, immortalized mouse microglial BV2 cells were treated with bacterial lipopolysaccharide (LPS) and exposed to conditioned media (CM) of naïve or IL-1-primed MSCs, and levels of secreted microglial-derived inflammatory mediators including TNF-α, IL-10, G-CSF and IL-6 were measured by ELISA.”).
However, Redondo-Castro does not teach expressly teach measuring the indicator of a response and classifying a therapeutic efficacy in mesenchymal stem cells.
Chang teaches a method of selecting high efficacy stem cells based on the expression of vascular endothelial growth factor for treating cerebrovascular disease (para 0007, “Thus, the present disclosure provides a method for selecting a high efficacy stem cell for treating a cerebrovascular disease, the method including a step of measuring a level of a VEGF and a high efficacy stem cell selected by the method.”; Claim 1, “A method for selecting a high efficacy stem cell for treating a cerebrovascular disease, the method comprising: measuring an expression level of a vascular endothelial growth factor (VEGF).”; Claim 2, “The method according to claim 1, wherein the method comprises: (a) culturing stem cells; (b) measuring a concentration of a VEGF in a culture solution of the stem cells in Step (a); and (c) evaluating an ability to protect nerve cells based on the measured concentration.”; Claim 3, “The method according to claim 3, wherein the evaluation of the ability to protect nerve cells is determined to be high efficacy when the measured concentration of the VEGF is 100 pg/ml or more.”).
It would have been obvious for an artisan with ordinary skill in the art to combine the method of measuring the indicator of a response and classifying a therapeutic efficacy in mesenchymal stem cells to determine whether a mesenchymal stem cell is highly therapeutic as taught by Chang, with the method of culturing MSCs in the presence of cytokines or growth factors and measuring anti-inflammatory potential of MSCs as taught by Redondo-Castro, for use in downstream applications such as treatment for disease. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
Regarding claim 1 and 33, the combined teachings of Redondo-Castro and Chang render obvious the claimed methodology of claim 32. Moreover, Redondo-Castro teaches measuring the levels of cytokines secreted by the MSCs (pp. 1, Abstract, “To confirm the anti-inflammatory potential of MSCs, immortalized mouse microglial BV2 cells were treated with bacterial lipopolysaccharide (LPS) and exposed to conditioned media (CM) of naïve or IL-1-primed MSCs, and levels of secreted microglial-derived inflammatory mediators including TNF-α, IL-10, G-CSF and IL-6 were measured by ELISA.”). Further, Redondo-Castro teaches that the MSCs showed greater expression of granulocyte macrophage colony stimulating factor (GM-CSF) (pp. 1, Abstract, “Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra.”).
Regarding claim 2, the combined teachings of Redondo-Castro and Chang et al. render obvious the claimed methodology of claim 1 and 32. Moreover, Redondo-Castro teaches that the MSCs increased rates of tissue remodeling (pp. 8, col 2, “Moreover, the increased secretion of G-CSF induced by MSCs induced an M2 or M2-like functional phenotype in macrophages (which implies an anti-inflammatory and pro regenerative phenotype) [44–46], as well as leading to higher rates of tissue remodeling and angiogenesis”).
Regarding claim 3, the combined teachings of Redondo-Castro and Chang et al. render obvious the claimed methodology of claim 1 and 32. Moreover, Redondo-Castro teaches that the biological source is from bone marrow (pp. 2, col 2, “Human bone marrow-derived MSCs were purchased from Lonza (UK) and 3H Biomedical (Sweden). Three different donors were used in this study”), and that the growth factor-associated with increased p-JNK level is granulocyte macrophage stimulating factor (GM-CSF). Further, Redondo-Castro teaches that the growth factor associated with the increased p-JNK level is GM-CSF (pp. 1, Abstract, “Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased increased secretion of G-CSF, which was blocked by IL-1Ra.”)
***
Claim(s) 1, 7, 10-12, 16-18, 20, 21, 25-27, and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Redondo-Castro (Published: 2017. Stem cell research & therapy, 8(1), 79. Cited in ISR filed 1/26/2024), in view of Chang et al. ( Published: 2019. US Publication: US 20190160105 A1) as applied to claim 1 and 32, and in further view of Sheng et al. (Published: 2016. Experimental and therapeutic medicine, 13(1), 55–62.) , Yang et al. (Published: 2011. J Biol Chem. 2011 Apr 15;286(15):13512-21.), Xing et al. (Published: 2020. Cell transplantation, 29, 963689720932142.).
With regard to claim 32, the combined teachings of Redondo-Castro and Chang render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 32.
However, the combined teachings fail to teach treating the highly therapeutic MSCs with an activator of the MAPK pathway and an inhibitor of the PI2K/Akt pathway, as required by claims 11 and 20.
Sheng teaches the effect of inhibiting the PI2K/AKT pathway, and its role in bone marrow MSC (BM-MSC) differentiation and proliferation (pp. 55 col 1, Abstract, “The present study aimed to analyze the role of PI3K/AKT pathway in hypoxia-induced proliferation of BM-MSCs and their differentiation into endothelial cells in vitro by the application of LY294002, a PI3K/AKT pathway inhibitor, with cells cultured in normoxia serving as a control”). Moreover, Sheng teaches that the activiation PI3K/Akt mediated pathway influenced MSC differentiation into endothelial cells (pp. 55 col 2, “In addition, the PI3K/AKT pathway-mediated cellular responses were examined, including proliferation, differentiation into endothelial cells and paracrine function.”). Further Sheng teaches that LY294002, a known PIK3/Akt pathway inhibitor, prevented the differentiation of BM-MSCs into endothelial cells (pp. 59, Fig. 3 Caption, “LY294002 inhibited the differentiation of BM-MSCs into endothelial cells”).
It would have been obvious to a skilled artisan to treat the highly therapeutic MSCs as taught by Chang and Redondo-Castro, with a PIK3/Akt inhibitor as taught by Sheng, as it was shown to prevent differentiation into endothelial lineages. Further, it would have been obvious to use the inhibitor to determine the effect of PI3K/Akt pathway on MSCs. Applying a known pathway modulator (PIK3/Akt pathway inhibitor) to a method of classifying highly therapeutic MSCs would have yielded predictable use of known elements to a known method. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
However, the combined teachings do not expressly teach using an MAPK pathway activator.
Yang teaches that activation of p85-MAPK pathway is responsible for deriving osteoblasts (pp. 783, col 2, “P38 is an important member of the mitogen-activated protein kinase superfamily (MAPK) [9]. It is capable of regulating such processes as cell proliferation…”; pp. 784 col 1, “Recent studies demonstrated that p38 is capable of regulating osteogenesis of MSCs and MSC-derived osteoblasts”). Moreover, Yang teaches that anisomycin, a p38-MAPK agonist, aids in MSC recruitment (pp. 783, Abstract, “Immunohistochemical analysis suggested that anisomycin promoted MSC recruitment in the distraction gap. In conclusion, this study demonstrated that local application of p38 agonist anisomycin can increase new bone formation during DO. This study may lead to a novel cell-based strategy for the improvement of bone regeneration”).
It would have been obvious to combine the treatment method of Sheng to further comprise treating the MSCs with anisomycin, as it promotes MSC recruitment and differentiation into osteogenic lineages. Such application of anisomycin would enhance the therapeutic efficacy of MSCs for downstream experiments involving osteogenic related diseases. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
The combined teachings fail to teach administering the treated highly therapeutic mesenchymal stem cells to a subject.
Xing teaches the administration of mesenchymal stem cells to an osteoarthritic join in rats to determine therapeutic efficacy (pp. 1, “Primed MSCs in 3D microcryogels can be considered as an improved delivery strategy for cell therapy in treating OA that minimizes cell dose while retaining therapeutic efficacy”).
It would have been obvious to combine the treatment method of Sheng to further comprise administering the treated MSCs to rats to determine their therapeutic efficacy. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
Regarding claim 7, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of claim 32. Moreover, Xing teaches administering MSCs for retaining therapeutic efficacy in treating osteoarthritis (pp. 1, “Primed MSCs in 3D microcryogels can be considered as an improved delivery strategy for cell therapy in treating OA that minimizes cell dose while retaining therapeutic efficacy”).
Moreover, Redondo-Castro teaches that the biological source is from bone marrow (pp. 2, col 2, “Human bone marrow-derived MSCs were purchased from Lonza (UK) and 3H Biomedical (Sweden). Three different donors were used in this study”), and that the growth factor-associated with increased p-JNK level is granulocyte macrophage stimulating factor (GM-CSF). Further, Redondo-Castro teaches that the growth factor associated with the increased p-JNK level is GM-CSF (pp. 1, Abstract, “Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra.”). Xing teaches intra-articular administration of the MSCs in the joint of a rat suffering from osteoarthritis (Figure 1, attached below)
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It would have been obvious to combine the method of Redondo-Castro for determining MSCs as highly therapeutic, wherein the MSCs are isolated from bone marrow, with the method of Xing of administering the MSCs to a subject to determine the therapeutic effects of the MSCs in vivo. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
Regarding claim 10, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of claim 1, 7 and 32. Moreover, Redondo-Castro teaches propagating the therapeutic MSCs (pp.1 Abstract, “Human MSCs from three different donors were cultured in vitro and treated with inflammatory mediators as follows: interleukin (IL)-1α, IL-1β, tumour necrosis factor alpha (TNF-α) or interferon-γ”).
Regarding claim 12, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of claim 1, 11 and 32. Moreover, Redondo-Castro teaches that the biological source is from bone marrow (pp. 2, col 2, “Human bone marrow-derived MSCs were purchased from Lonza (UK) and 3H Biomedical (Sweden). Three different donors were used in this study”), and that the growth factor-associated with increased p-JNK level is granulocyte macrophage stimulating factor (GM-CSF). Further, Redondo-Castro teaches that the growth factor associated with the increased p-JNK level is GM-CSF (pp. 1, Abstract, “Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra.”).
Regarding claim 16 and 17, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 11 and 32. Moreover, Yang teaches that the activator of the MAPK pathway is a JNK activator, anisomycin (pp. 783, Abstract, “Immunohistochemical analysis suggested that anisomycin promoted MSC recruitment in the distraction gap. In conclusion, this study demonstrated that local application of p38 agonist anisomycin can increase new bone formation during DO. This study may lead to a novel cell-based strategy for the improvement of bone regeneration”).
Regarding claim 18, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 11 and 32. Moreover, Sheng teaches that LY294002, a known PIK3/Akt pathway inhibitor (pp. 59, Fig. 3 Caption, “LY294002 inhibited the differentiation of BM-MSCs into endothelial cells”).
Regarding claim 21, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of claim 1, 20 and 32. Moreover, Redondo-Castro teaches that the biological source is from bone marrow (pp. 2, col 2, “Human bone marrow-derived MSCs were purchased from Lonza (UK) and 3H Biomedical (Sweden). Three different donors were used in this study”), and that the growth factor-associated with increased p-JNK level is granulocyte macrophage stimulating factor (GM-CSF). Further, Redondo-Castro teaches that the growth factor associated with the increased p-JNK level is GM-CSF (pp. 1, Abstract, “Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra.”). Regarding claim 25 and 26, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 20 and 32. Moreover, Yang teaches that the activator of the MAPK pathway is a JNK activator, anisomycin (pp. 783, Abstract, “Immunohistochemical analysis suggested that anisomycin promoted MSC recruitment in the distraction gap. In conclusion, this study demonstrated that local application of p38 agonist anisomycin can increase new bone formation during DO. This study may lead to a novel cell-based strategy for the improvement of bone regeneration”).
Regarding claim 27, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 20 and 32. Moreover, Sheng teaches that LY294002, a known PIK3/Akt pathway inhibitor (pp. 59, Fig. 3 Caption, “LY294002 inhibited the differentiation of BM-MSCs into endothelial cells”).
Regarding claim 29, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 20 and 32. Moreover, Xing teaches intra-articular administration of the MSCs in the joint of a rat suffering from osteoarthritis (Figure 1, attached below)
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Regarding claim 30, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 20 and 32. Moreover, Moreover, Xing teaches intra-articular administration of the MSCs in the joint of a rat suffering from osteoarthritis (Figure 1, attached).
Regarding claim 31, the combined teachings of Redondo-Castro and Chang, Sheng, Yang and Xing render obvious the claimed methodology of 1, 20, 30 and 32. Moreover, Xing teaches administering the MSCs in humans (pp. 2, col 1, “Preclinical and clinical studies have recently demonstrated some favorable effects on cartilage repair when MSCs were injected into OA joints in animal models8 and in humans”).
***
Claim(s) 1, 11, 19, 28 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Redondo-Castro (Published: 2017. Stem cell research & therapy, 8(1), 79. Cited in ISR filed 1/26/2024), in view of Chang et al. ( Published: 2019. US Publication: US 20190160105 A1) as applied to claim 32, and further in view of Sheng et al. (Published: 2016. Experimental and therapeutic medicine, 13(1), 55–62.) and Yang et al. (Published: 2011. J Biol Chem. 2011 Apr 15;286(15):13512-21.) and Xing et al. (Published: 2020. Cell transplantation, 29, 963689720932142.), as applied to claims 11, 18, 27 and 20, in further view of National Cancer Institute (Published 2011. National Cancer Institute, Drug Dictionary).
With regard to claim 32, the combined teachings of Redondo-Castro, Chang, Sheng and Yang render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 32. Further, Sheng teaches that LY294002, a known PIK3/Akt pathway inhibitor, prevented the differentiation of BM-MSCs into endothelial cells (pp. 59, Fig. 3 Caption, “LY294002 inhibited the differentiation of BM-MSCs into endothelial cells”).
However, the combined teachings fail to teach that the AKT inhibitor is MK-2206, as required by claims 19 and 28.
National Cancer Institute teaches that MK-2206 is an inhibitor of the AKT pathway (“An orally bioavailable allosteric inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Akt inhibitor MK2206 binds to and inhibits the activity of Akt in a non-ATP competitive manner, which may result in the inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents.”).
Therefore, it would have been obvious to substitute the MK-2206 with the LY294002, as they are known inhibitors of the PI3K/AKT signaling pathway. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
Conclusion
No claims allowed.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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