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
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 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.
Response to Amendments
Applicant’s amendments, corrected specification, and response filed Jul. 28, 2026 have been received and entered into the case.
Status of the Claims
Claims 1, 3, 4, 11, 16, 18, 41, 42, and 44-47 are currently pending.
Claims 1, 3-4, 11, 16 and 41 are amended.
Claims 18 and 44-47 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 2, 5-10, 12-15, 17, 19-40, 43, and 48 are cancelled.
Claims 49-52 are new.
Claims 1, 3, 4, 11, 16, 41-42 and 49-52 have been considered on the merits.
Specification Objections
Specification objections are withdrawn due to amendment.
Claim Objections
The claim objections are withdrawn due to amendment. New claim objections have been added to address the claim amendments.
The disclosure is objected to because of the following informalities:
Claim 50 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 4. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Appropriate correction is appreciated.
Claim Rejections - 35 USC § 112 (a) written description
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) written description, are withdrawn due to amendment. New claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) have been added after further consideration.
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, 3, 4, 11, 16, 41-42 and 49-52 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 claims contain 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 pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention.
Claim 1 recites an “in vitro population of replication competent mesenchymal stem cells (MSCs), comprising increased secretion as compared to a naturally occurring MSC of insulin like growth factor binding protein 1 (IGFBP-1), and neurotrophin 3 (NT-3)”. However, the specification describes in Example 2, the Sephax® isolation of mononuclear cells from bone marrow aspirates (see 0194-0195 of published application). The MNC are than seeded at a density of 5000-8000 cells/cm2, and cultured in NutriStem® MSC XF media supplemented with 10% Glutamax®, 0.5% non-essential amino acids, and 1% non-essential vitamins listed in Table 1. Half of the medium is replaced with fresh medium every 48 hrs in culture so that the entire medium is never removed, the cells are never exposed to air and the dish is never washed and until the cells reached 90% confluence.
It is these replication competent mononuclear cells that are described to have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 as described in Example 3 and Table 2 of the published specification.
The specification does not describe isolating mesenchymal stem cells and culturing the cells to produce replication competent mesenchymal stem cells which have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The specification does not disclose what conditions can be used to stimulate isolated mesenchymal stem cells to have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The specification and the claims do not provide any guidance on what method can be used to generate mesenchymal stem cells with an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The only clear method of producing cells that have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 appear to be mononuclear cells isolated from bone marrow aspirates.
The purpose of the written description requirement is to ensure that the invention had possession, as of the filing date of the application, of the specific subject matter later claimed by him or her. A patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention. The specification lacks description of what conditions can be used to produce replication competent mesenchymal stem cells that have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 and does not provide any examples of such cells. Accordingly, the specification fails to provide adequate written description for the “replication competent mesenchymal stem cells that have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3”, and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed had possession of the entire scope of the claimed invention. Thus, the written description requirement has not been satisfied.
Claim Rejections - 35 USC § 112 (a) enablement
New claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) enablement have been added after further consideration.
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, 3, 4, 11, 16, 41-42 and 49-52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for replication competent mononuclear cells (MNCs) that have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 and are produced by method of
isolating MNCs from bone marrow aspirates by Sephax® density separation, seeding the isolated MNCs at a density of 5000-8000 cells/cm2,
culturing the cells in NutriStem® MSC XF media supplemented with 10% Glutamax®, 0.5% non-essential amino acids, and 1% non-essential vitamins (biotin, D-calcium pantothenate, choline chloride, folic acid, i-Inositol, niacinamide, pyridoxal hydrochloride pyridoxine hydrochloride, riboflavin, thiamine hydrochloride, and vitamin B12), and
replacing the half medium with fresh medium every 48 hours in culture so that the entire medium is never removed, the cells are never exposed to air and the dish is never washed and until the cells reached 90% confluence.
The specification does not reasonably provide enablement for replication competent mesenchymal stem cells that have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). 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 is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the 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). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to mesenchymal stem cells that have an increased secretion as compared to a naturally occurring mesenchymal stem cell of IGFBP-1 and NT-3. Thus, the claims taken together with the specification imply that any kind of mesenchymal stem cell can be made to have an increase in the secretion of IGFBP-1 and NT-3 as compared to a naturally occurring mesenchymal stem cells.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art in general teaches that different cell sources often have distinct biological properties, differentiation potentials, and markers and that different culturing methods can induce cells to secrete different factors. For instance, Issa et al. (Journal of Neuropathology & Experimental Neurology, 2025) reports on the many different mesenchymal stem cells (MSCs) from different tissue sources and the different effects the different sourced MSCs cells have on different diseases (see entire article). Additionally, Hass et al. (Cell Communication and Signaling, 2011) reports on the different populations and sources of mesenchymal stem cells and reports that the different populations express different markers and have different differentiation capacity and plasticity (see entire article and Table 1). In further support, Gothelf et al. (WO 2014/024183 A1) reports that “mesenchymal stem cells following exposure to different factors in vitro can change their phenotype and demonstrate neuronal and glial markers” (pg. 2 lines 5-7) and reports a particular method of differentiating MSCs into MSC-NFT secreting cells involving particular conditions and factors (pg. 43 line 3 to pg. 44 line 5). Therefore, there is a high level of unpredictability in the art for producing cells expressing and secreting particular proteins.
Thus, as the state of the art stands, the method would be unpredictable depending on many factors including the specific mesenchymal stem cell type being used and the culturing conditions. Therefore, without guidance from the specification the production of replication competent mesenchymal stem cells with increased secretion of IGFBP-1 and NT-3 as compared to a naturally occurring mesenchymal stem cells is unpredictable and would require undue experimentation.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The instant specification provides working examples and guidance for the production of bone marrow mononuclear cells that have an increased secretion as compared to a naturally occurring mesenchymal stem cells of IGFBP-1 and NT-3. However, the specification does not provide any guidance for the production of mesenchymal stem cells with an increased secretion as compared to a naturally occurring mesenchymal stem cells of IGFBP-1 and NT-3. The applicants have provided neither data nor any conditions for producing the claimed mesenchymal stem cells to give the skilled artisan any reason to expect that the claimed mesenchymal stem cells could be easily produced.
Specifically, the specification describes in Example 2, the Sephax® isolation of mononuclear cells from bone marrow aspirates (see 0194-0195 of published application). The MNC are than seeded at a density of 5000-8000 cells/cm2, and cultured in NutriStem® MSC XF media supplemented with 10% Glutamax®, 0.5% non-essential amino acids, and 1% non-essential vitamins listed in Table 1. Half of the medium is replaced with fresh medium every 48 hrs in culture so that the entire medium is never removed, the cells are never exposed to air and the dish is never washed and until the cells reached 90% confluence.
It is these replication competent mononuclear cells that are described to have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 as described in Example 3 and Table 2 of the published specification. The specification does not describe or provide guidance for isolating mesenchymal stem cells from any tissue source and culturing the cells to produce replication competent mesenchymal stem cells which have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The specification does not disclose what conditions can be used to stimulate isolated mesenchymal stem cells to have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The specification and the claims do not provide any guidance on what method can be used to generate mesenchymal stem cells with an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3. The only clear method of producing cells that have an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 appear to be mononuclear cells isolated from bone marrow aspirates.
There is no conclusive evidence in the instant disclosure to indicate that the claimed mesenchymal stem cells can be made.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to produce the claimed invention within the broad scope as instantly claimed. The single disclosed method for producing bone marrow-derived mononuclear with an increased secretion as compared to a naturally occurring MSC of IGFBP-1 and NT-3 does not allow a skilled artisan to reach the claimed mesenchymal stem cell without excessive trial and error.
Claim Rejections - 35 USC § 112(b)
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment. New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added to address the claim amendments.
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 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.
In claim 49, line 1, the phrase "eMSC" lacks sufficient antecedent basis and renders the claim and its dependents indefinite.
All other claims depend directly or indirectly from rejected claims and are, therefore, also rejected under USC 112 for the reasons set forth above.
Appropriate correction is required.
Claim Rejections - 35 USC § 102/103
The claim rejections under 35 USC § 102/103 are withdrawn due to amendment.
Response to Arguments
Applicant’s arguments, see Remarks, filed Jul. 28, 2026, with respect to the rejections of claims 1, 3-4, 11, 16, 41-42 and 49-52 under 35 U.S.C. § 102/103 have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new grounds of rejections are made under 35 U.S.C. § 112 (a) written description and scope of enablement.
Specifically, with respect to the rejections under 35 U.S.C. § 102/103, Applicant argues that Celebi 2012 doesn’t make use of or even study MSCs, but instead tests the effects of IGFBP2 and NT-3 on HSCs. Applicant argues that Celebi’s 2011 paper that is referenced in Celebi 2012 that discloses irradiated MSCs that secrete increased levels NT-3 and the cells are irradiated so they stop replicating so that they can be used as feeder cells for HSCs (Remarks pg. 11 last para.). Applicant argues in contrast to Celebi, the claimed cells are proliferating cells as evident in the Examples section where the passaging of the cells is discussed (Remarks pg. 12 para. 1). Applicant argues that no combination with Celebi with any other references to arrive at the claimed invention, since it is the irradiation of the cells in Celebi which causes the MSCs to have increased NT-3 secretion (Remarks pg. 12 para. 2). Applicant’s arguments are drawn to Celebi failing to teach this new limitation.
With respect to the rejections under 35 U.S.C. § 102/103, Applicant argues that Lee doesn’t actually teach cells with higher levels of NT-3, but states that the sphere culture did not significantly increase NT-3 secretion (Remarks pg. 12 last para. to pg. 13 para. 1). This argument was found to be persuasive.
Applicant further argues that since the only prior art teaches MSCs with increased NT-3 secretion are irradiated MSCs are not replication competent there is no single piece or combination of art that teaches all of limitations of claim 1 (Remarks pg. 13 para. 3). This argument is drawn to Celebi failing to teach this new limitation.
Applicant argues that the claims require the MSCs to be devoid of CD146 and MSCs is known to be expressed on a wide variety of MSCs. Applicant argues that Lee uses MSCs derived from embryonic stem cells which are known to be CD146 positive as evidenced by Chin which reports that all MSCs are CD146 positive (Remarks pg. 13 para. 4). This argument was considered, but is moot since Lee is no longer being used as prior art in a rejection.
Applicant argues that with respect to claims 3 and 16, SSEA-5 and CD206 are not reported to be expressed by MSCs and to the best of their knowledge there are no known cells that are double positive for SSEA-5 and CD206 (Remarks pg. 13 para. 5). Applicant’s arguments are drawn to cited prior failing to teach this new limitation.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
