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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/17/2025 has been entered.
Response to Amendment
The amendment filed 11/17/2025, amending claim(s) 1, 5, 15, and 19 and newly adding claim(s) 49 and 50 is acknowledged. The 112(b) and 112(d) rejections previously set forth in the Final Office Action mailed 8/25/2025 are withdrawn. The replacement drawing (Fig. 1) filed 7/11/2025 is not accepted. See objection below.
Claims 1, 5, 15, 19, and 45-50 are pending.
Claims 45-48 remain withdrawn.
Claims 1, 5, 15, 19, 49, and 50 are pending and under examination.
Withdrawn Rejections
The rejections of claims 1 and 5 under 35 U.S.C. 102(a)(1) as being anticipated by Mailliard, and of claims 15 and 19 under 35 U.S.C. 103 as being unpatentable over Mailliard and Han is withdrawn.
Mailliard does not disclose the new limitation “A composition for creating an isolated population of mesenchymal stem cells (MSCs) having an anti-inflammatory phenotype consisting essentially of: an unprimed population of MSCs”, which is now required in independent claims 1 and 15.
Response to Arguments
Applicant's arguments filed 11/17/2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to claim(s) 1, 5, 15, and have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Information Disclosure Statement
The information disclosure statement filed 2/03/2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Drawings - Maintained
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the upregulation (red) and downregulation (green) of a network of cytokine pathways in Figure 1 as described in [0021] of the specification. The replacement drawing submitted 11/17/2025 is smaller, blurrier, and still fails to show the red and green components of the figure as described in [0021] (i.e., the drawing is not in color, so it is unknown what is a red component vs. green componsnet). Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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 Interpretation
Claims 1 and 15 recite “a priming medium for creating an isolated population of mesenchymal stem cells (MSCs) having an anti-inflammatory phenotype”. The examiner notes that the recitation of “for creating an isolated population of MSCs having an anti-inflammatory phenotype” in the preamble is interpreted as an intended use of the claimed invention and not a limitation of the claimed invention. “For creating an isolated population of MSCs having an anti-inflammatory phenotype” does not limit the structure of the claimed invention; therefore, it does not provide significance to the claim construction. See MPEP § 2111.02.II.
The claims recite “MSCs having an anti-inflammatory phenotype” and “wherein the MSCs having an anti-inflammatory phenotype are marked by increased expression and/or secretion of one or more anti-inflammatory or immune modulatory mediators as compared to the unprimed population of MSCs”. Additionally, claims 49 and 50 recite “wherein the MSCs have an anti- inflammatory phenotype with enhanced angiogenic potential and superior tissue repair capabilities and comprise surface expression of CD146+ and Lep-R+.” [0092] of the specification recites:
“As used herein, the term "anti-inflammatory phenotype" can refer to the conglomerate of multiple cellular processes involving gene and protein expression that result in a cell's particular morphological and functional characteristics which, as a result of culture with a priming medium of the present disclosure, produce a cell marked or characterized by increased expression and/or secretion of one or more anti-inflammatory or immune modulatory mediators or markers as compared to a cell that has not been contacted with a priming medium of the present disclosure.”
The broadest reasonable interpretation of this recitation includes the stem cells possessing any phenotype (i.e., trait, characteristic) associated with anti-inflammatory activity and/or sharing any property with any cell associated with resolving inflammation, such as macrophages and Tregs, These traits/properties include but are not limited to gene expression, cell shape, comprising the same organelle(s) (i.e., a nucleus), etc.
Additionally, claims 1 and 15 are newly amended to recite the transitional phrase "consisting essentially of" excludes any element, step, or ingredient not specified in the claim. According to MPEP § 2111.03:
“The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976)…
For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355…
If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of "consisting essentially of," applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of the claimed invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964).”
Claim Rejections - 35 USC § 112(a) – Modified, necessitated by amendment
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1, 5, 15, 19, 49, and 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 15 recite: “wherein the MSCs having an anti-inflammatory phenotype are marked by increased expression and/or secretion of one or more anti-inflammatory or immune modulatory mediators as compared to the unprimed population of MSCs.”
Claims 5 and 19 recite: “wherein the MSCs havinq an anti-inflammatory phenotype comprise surface expression of CD146+ and Lep-R+.”
Claims 49 and 50 recite: “wherein the MSCs have an anti- inflammatory phenotype with enhanced angiogenic potential and superior tissue repair capabilities and comprise surface expression of CD146+ and Lep-R+.”
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Either these are inherent properties of (that naturally flows from) the structure of claims 1 and 15, or they are not.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the MSCs to possess these characteristics/marker profiles. The claim limitations recited above merely state functional characteristics without providing any indication about how the characteristic is provided. The characteristic does not follow from (is not an inherent property of) the structure recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition to provide the characteristic.
The specification fails to disclose what structural changes to the composition is/are necessary and sufficient to cause the recited function of promoting induction of MSCs having an anti-inflammatory phenotype, wherein the MSCs having an anti-inflammatory phenotype are marked by increased expression and/or secretion of one or more anti-inflammatory or immune modulatory mediators as compared to the unprimed population of MSCs, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
Further, the compositions of claims 1 and 15 differ in that claim 15, in addition to the same structures recited in claim 1, an additionally at least four pro-inflammatory cytokines, adding in IL-1B and IL-17A, and an essential vitamin. However, claims 1 and 15, 5 and 19, and 49 and 50, respectively, are parallel in reciting identical resulting functions of the MSCs created. As such, an artisan is left to wonder what structures are required to create the MSCs having an anti-inflammatory phenotype. For example, if IL-17A and IL-1B necessary structurally to result in MSCs having an anti-inflammatory phenotype, why are they only required in one composition (claim 15) and not the other (claim 1)?
Additionally, the priming medium(s) of the composition are recited at a high level of generality, e.g., no positively recited concentration(s).
The recitation of the priming mediums recited in claims 1 and 15 are far broader in scope than the working examples of the specification. For example, [00188] recites treating MSCs with danger signals, such as Poly (I:C) (30 ng/ml), Lipopolysaccharide (LPS) (10ug/ml), TNF-a (50ng/ml), and IL-1B (25ng/ml) over night (18 hours). Additionally, [00214] recites the following cytokines and concentrations: TNF-a (20 ng/ml), IFN-a (20ng/ml), IFN-B (l0ng/ml), PDGF-BB (long/ml), IFN-y (100 ng/ml), IL-13 (10 ng/ml), IL-17A (50 ng/ml), Ascorbic acid 2 phosphate (200uM), Poly I:C (1 ug/ml), TGF-(3 (10 ng/ml), EGF (20ng/ml) and Vitamin D3 (10ng/ml). Further, [00218-00224] recites:
“Based on the foregoing experimental results, it was surprisingly discovered that HXB-319, which had the following formulation, could be used to induce or prime MSCs to obtain an anti-inflammatory phenotype to specifically regulate immune cellular activity and improve immune cell dysfunction after Type I and Type II interferon pathway induction (e.g., by autoimmunity):
interferon-gamma, 100ng/ml (eBioscience (BMS303));
Poly (I:C), lug/ml (Sigma Aldrich (9582-5mg);
tumor necrosis factor-a, 20ng/ml (Peprotech (300-01A-50ug));
interleukin 1-B, 10ng/ml, (Peprotech (200-O1b-l0ug));
interleukin -17-A, 50ng/ml (Peprotech (200-17)); and
ASC-AC-21, 200 pM (Sigma-Alrich (L4524-5MG))”
The claims fail to recite, and the specification fails to disclose, a nexus between the required serum-free priming medium(s) consisting essentially of Poly(I:C), and at least pro-inflammatory cytokines IFN-y and TNF-a (and IL-1B, I-17A) and the corresponding functional property(ies) of promoting induction of MSCs having an anti-inflammatory phenotypes, and the MSCs having an anti-inflammatory phenotype are marked by increased expression and/or secretion of one or more anti-inflammatory or immune modulatory mediators as compared to the unprimed population of MSCs.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first serum-free priming medium consisting of Poly(I:C), and at least pro-inflammatory cytokines IFN-y and TNF-a, that is unable to promote induction of MSCs having an anti-inflammatory phenotypes, transforms said first serum-free priming medium consisting of Poly(I:C), and at least pro-inflammatory cytokines IFN-y and TNF-a, into one that is now necessarily and predictably capable of promoting induction of MSCs having an anti-inflammatory phenotypes.
Further, the claims fail to recite, and the specification fails to disclose what modification(s) to a priming medium that is unable to produce a cell having the function of expressing CD146+ and Lep-R+, transforms said priming medium into one that is now necessarily and predictably capable of producing an MSC that expresses CD146+ and Lep-R+, for example.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Mancheno-Corvo, Pablo, et al. "T lymphocyte pre-stimulation impairs in a time-dependent manner the capacity of adipose mesenchymal stem cells to inhibit proliferation: role of interferon γ, poly I: C, and tryptophan metabolism in restoring adipose mesenchymal stem cell inhibitory effect." Stem Cells and Development 24.18 (2015): 2158-2170. is considered relevant prior art for studying the immunoproperties of MSCs. In Mancheno-Corvo et al., ASCs (adipose MSCs) were activated with different stimuli: IFN-g (3, 0.3 or 0.03ng/mL), TNF-a (20ng/mL), IL-1b (20ng/ mL), LPS (10mg/mL), Poly I:C (1 or 10mg/mL), TGF-b (10ng/mL), SDF-1a (150ng/mL), and IL-17 (50ng/mL) (pg. 2160, col 1, para 3). The group found that preactivation of ASCs for 48h with IFN-g and, to a lesser extent, with Poly I:C (but not with TNF-a, IL 1b, TGF-b, SDF-1a, IL-17, or LPS) allowed ASCs to inhibit the proliferation of 48h-prestimulated lymphocytes if the coculture was done in the medium conditioned by pre activated ASCs. Among all the stimuli tested, only IFN-g and Poly I:C induced IDO activity (Fig. 5) (pg. 2167, col 2, para 6). Mancheno-Corvo et al. note that synergistic/combinatorial effects between cytokines should also be considered, as IL-17 did not enhance the inhibitory effects of ASCs in their experiments, but has been recently reported to enhance the immunosuppressive effect of MSCs activated by IFN-g +TNF-a (pg. 2168, col 1, para 6).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph, and the Artisan would not have understood Applicant to have been in possession of the invention as claimed.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
Claim Rejections - 35 USC § 112(b)
Claims 1, 5, 15, 19, 49, and 50 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.
Claims 1 and 15 recite “a composition for creating an isolated population of mesenchymal stem cells (MSCs) having an anti-inflammatory phenotype”. It is unclear what the metes and bounds of this recitation is. For example, what does a “phenotype” cell population encompass? What is considered an anti-inflammatory phenotype? What properties (and how many) must the cell population share to be considered to have an anti-inflammatory phenotype? It would be remedial to clarify what is considered an anti-inflammatory phenotype.
Claims 49 and 50 recite “enhanced angiogenic potential” and “superior tissue repair capabilities”. It is unclear what the metes and bounds of this recitation is. What does “angiogenic potential” and “tissue repair capabilities” encompass? Is expressing CD146 and Lep-R enough to be considered to possess “enhanced angiogenic potential” and “superior tissue repair capabilities”? It would be remedial to amend the claims to recite what specific structure read on “enhanced angiogenic potential” and “superior tissue repair capabilities”.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 103 – New, necessitated by amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 5, 15, 19, 49 and 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Noronha (Noronha, Nádia de Cássia, et al. "Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies." Stem cell research & therapy 10.1 (2019): 131.).
Regarding claims 1 and 15, Noronha et al. disclose that under inflammatory conditions, MSCs mainly enriched by pro-inflammatory cytokines interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), and interleukin-1 (IL-1β) are “licensed/activated/primed,” thereby upregulate class I/II MHC and costimulatory molecules, display improved proliferation and survival conditions, and acquire enhanced immunomodulatory and immunosuppressive functions (pg. 2, col 1, para 2; Fig. 2).
Noronha et al. also teaches multiple studies where MSC derived from adipose tissue, bone marrow, foreskin, or Wharton’s jelly, primed with an pro-inflammatory cytokine cocktail (IL-1β, TNF-α, IFN-α, and IFN-γ), presented different expression levels of the immunoregulatory genes FGL2, GAL, SEMA4D, SEMA7A, and IDO1 (pg. 6, col 1, para 3). Further, Noronha et al. teaches that non-selective (or non-specific) priming approaches, such as poly (I:C), can stimulate wide effector molecules and signaling path ways, and priming with Poly(I:C) directs MSC polarization into an immunosuppressive phenotype through TLR3 activation (pg. 14, col 1, “MSC priming with other molecules”).
As previously mentioned in the Non-Final Office Action mailed 04/22/2025, MEM and DMEM media, both well known and commonly used mediums in the art, contain essential vitamins such as folic acid and riboflavin- see previous Thermo Fisher NPL.
Noronha et al. also teaches the MSCs having an anti-inflammatory phenotype marked by characteristics such as increased T cell immunosuppressive capacity mediated by inducible nitric oxide synthase (iNOS) production. Additionally, Naoronha et al. teach the MSCs having “enhanced angiogenic potential” and “superior tissue repair capabilities” via reduced inflammation and tissue injury (pg. 6, col 1, para 3).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the different methods taught by Noronha et al. by adding poly(I:C) to an pro-inflammatory cytokine cocktail (IL-1β, TNF-α, IFN-α, and IFN-γ) that MSCs are primed in to arrive at the claimed invention. It would have amounted to a further simple combination of prior art elements by known means to yield predictable results, resulting in the claimed invention. An artisan would have been motivated to add poly(I:c) to the priming media because as taught by Noronha et al., priming with poly(I:C) directs MSC polarization into an immunosuppressive phenotype through TLR3 activation (pg. 14, col 1, “MSC priming with other molecules”).
Noronha et al. does not teach the MSCs having an anti-inflammatory phenotype comprising surface expression of CD146+ and Lep-R+.
However, the combined teachings of Noronha et al. teach all structures of the claimed composition, and there is nothing to suggest that the MSCs of the composition would not also have these characteristics if tested. For example, Noronha et al. teaches MSCs primed with IFN-y expressing similar factors to CD146 (as known as MCAM), such as adhesion proteins VCAM-1 and ICAM-1 (the reference is silent on the expression of MCAM).
As previously discussed in the prior office action, the claiming of an unknown property (e.g., expression of CD146+ and Lep-R+) which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
"In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art." Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990) (emphasis in original).
Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evident or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference. MPEP §2112. "[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on 'inherency' under 35 U.S.C. 102, on 'prima facie obviousness' under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted]." The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638