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 .
The Examiner notes that the Notice of Non-Compliant Amendment, mailed 01/06/2026, is vacated and replaced by this Non-Final Office Action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/07/2025 has been entered.
Response to Amendment
The amendment filed 07/07/2025, amending claim 1, canceling claims 4, 5, 7, 14-21, and adding claims 22-25 is acknowledged.
In light of the Applicant’s amendments to independent claim 1, which now requires “CD14+”, the Examiner withdraws the restriction requirement between species “CD14+” and “interferon gamma receptor”, rejoining non-elected species “CD14+” with the elected species “interferon gamma receptor”.
Claims 1-3, 6, 8-13, and 22-25 are pending. Claims 1 and 13 are under examination. Claims 22-25 are withdrawn due to being drawn to non-elected species (newly added claim 22 recites the same limitation as canceled claim 15, which was previously withdrawn; newly added claims 23-25 recite the same limitations as canceled claims 18-20, respectively, which were previously withdrawn).
Applicant’s amendments to the claims have overcome the claim objection previously set forth in the Final Office Action mailed 01/06/2025.
The amendment to the claims filed on 07/07/2025 does not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The correct status of claims 22-25 is (New, Withdrawn).
Withdrawn Rejections
The rejection of claims 1 and 13 under 1112(a) regarding “capable of” is withdrawn, as the Applicant has clarified that “capable of suppression of inflammation and activation of endogenous regenerative cells” is an inherent functional property of the steps/structure of the claims (see further discussion in Response to Arguments below).
Priority
Applicant’s claim for the benefit of a prior-filed application provisional application 63/223,245, filed on July 19th, 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/223,245, filed on July 19th, 2021 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the pa-tent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [provisional application]. Thus, [provisional application] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
With respect to Claim 1, ‘245 fails to disclose a monocytic cell population isolated by positive selection of CD14+ and interferon gamma receptor together (i.e., the two are never recited in the same method step, only as separate, independent embodiments).
There are no blaze marks to select CD14+ and interferon gamma receptor together. Further, there are no working examples where a monocytic cell population are isolated via positive selection for CD14+ or interferon gamma receptor, let alone together.
United States Court of Appeals for the Federal Circuit, FWP IP APS v. Biogen MA, Inc (Case 2017-2109; decided October 24, 2018).
Piecing together elements of several claims and/or disparate portions of the specification to arrive at the specifically claimed subject matter does not satisfy the written description requirement. The task of locating the now-claimed subject matter within the original claims is made uncommonly more difficult by the original claims themselves, which are written in a cascading, multiple dependencies manner such that many of them generically refer back to any one of the preceding claims. Title 35 forbids this type of claim drafting because it can—as here—lead to bizarrely complex chains of cross-referencing claims in which one multiple dependent claim impermissibly serves as a basis for other multiple dependent claims. Finding the presently recited combination of specific experimental parameters, including the specific combination of disparate subgenus experimental parameters “in the morass of possible combinations of the impermissibly-drafted original claims would-- as Judge Learned Hand
observed in a different but related context—take “the patience of a yogi to decipher their meaning, as they stand.” Victor Talking Mach. Co. v. Thomas A. Edison, Inc., 229 F. 999, 1001 (2d Cir. 1916). A review of the claims and their intermixing dependencies presents an overall picture of a set of claims designed to preempt a conspicuously large number of different dosage regimens for a large variety of conditions using a long list of formulations, which is disconnected from a written description that is far more limited in its disclosure.
The disclosure of 62/020,163 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application.
The disclosures of 14/790,562 filed on July 2, 2015 and 15/495,157 filed on April 24, 2017, having the same specification as ‘163, are similarly deficient.
Originally presented claims in 62/020,163, 14/790,562, and 15/495,157 suffer from impermissible multiple dependent claims.
Accordingly, the effective priority date of claims 1 and 13 is granted as the filing date of the instant application, July 15th, 2022.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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 and 13 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.
Newly amended claim 1 recites:
“A method of generating a monocytic lineage cell capable of suppressing inflammation and inducing activation of endogenous regenerative cells, comprising:
a) obtaining a monocytic population that is isolated by positive selection for interferon gamma receptor and CD14+;
b) obtaining subepithelial umbilical cord derived mesenchymal stem cells and treating them with interferon gamma;
c) creating conditioned media from said treated mesenchymal stem cells; and d) culturing said monocytic cell population in said conditioned media.”.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [63/223,245]. Thus, [63/223,245] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
The disclosure of 63/223,245 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application. Additionally, the disclosure of 63/223,245 does not disclose or suggest using a combination of markers to isolate monocytic cells, obtaining subepithelial umbilical cord mesenchymal stem cells, nor method step (b) alone and/or in combination with step(s) (a), (c), and/or (d).
The amendments to claim 1 introduced new matter, as the content of the claim is not described as filed. The specification fails to describe or provide evidence of possessing a method where the monocytic population is isolated by positive selection for interferon gamma receptor and CD14+ (i.e., using multiple markers to isolate monocytic cells).
When searching for “CD14” in the specification, the only/closest results returned are unrelated to isolation of monocytic cells (e.g., reciting cell types that lack substantial expression of CD14- [00187, 00212, 00214]; [001074]; preparation of subepithelial cord tissue stem cells- [00241, 00252]).
When searching for “interferon” or “gamma” in the specification, the only/closest results returned are either unrelated to isolation of monocytic cells (e.g., recitations are related to elevated concentrations of interferon gamma and inflammation – [0061-0065]; antibody crosslinks interferon gamma receptor – [00933]) or reiterate the claim language (e.g., [00359]).
Further, there are no working examples disclosed in the instant specification where interferon gamma receptor and/or CD14+ were used to isolate monocytic cells.
In summary, the specification does not disclose or teach using more than one factor to positively select a monocytic cell population in a method (i.e., there are no blaze marks to isolate a monocytic cell population by positive selection for interferon gamma receptor and CD14+).
Additionally, the specification fails to describe or provide evidence of possessing a method comprising a step of “obtaining subepithelial umbilical cord derived mesenchymal stem cells”. A search for “subepithelial” in the specification only returned results reciting “subepithelial cord tissue stem cells” (i.e., not subepithelial umbilical cord derived mesenchymal stem cells) (e.g., [00241]). Further, the specification distinguishes between “subepithelial umbilical cord tissue stem cells” and “mesenchymal stem cells”, for example (e.g., [00588]). The specification also teaches two different methods for preparing the differing cell types:
[00734] Preferred methods include embodiments wherein said mesenchymal stem cells are generated from pluripotent stem cells by a) culturing single cells in the presence of at least one growth factor in an amount sufficient to induce the differentiation of said clusters of cells into mesenchymal stem cells; b) adding one or more of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), bone morphogenic protein 4(BMP-4), stem cell factor (SCF), Flt 3L (FL), thrombopoietin (TPO), EPO, and/or tPTD-HOXB4. The one or more of said at least one growth factor added in step (b) may be added to said culture within 36-60 hours from the start of step (a) (i.e., claim 13)
[00735] Preferred methods include embodiments wherein said subepithelial cord tissue stem cells are prepared by a process comprising: placing a subepithelial layer of a mammalian umbilical cord tissue in direct contact with a growth substrate; and culturing the subepithelial layer such that the isolated cell from the subepithelial layer is capable of self-renewal and culture expansion, wherein the isolated cell expresses at least three cell markers selected from the group consisting of CD29, CD73, CD90, CD 166,SSEA4, CD9, CD44, CD 146, or CD 105, and wherein the isolated cell does not express NANOG and at least five cell markers selected from the group consisting of CD45, CD34, CD14, CD79, CD106, CD86, CD80, CD19, CD117, Stro-1, or HLA-DR.
As such, the specification also lacks support/direction for generating subepithelial cord derived mesenchymal stem cells from pluripotent stem cells (the recitation of “mesenchymal stem cells” in claim 13 is interpreted to read on “subepithelial cord derived mesenchymal stem cells” since claim 13 depends upon claim 1). No guidance is provided for the ordinary artisan to determine whether the same steps of claim 13 would result in “subepithelial cord derived mesenchymal stem cells” being generated (and if they would result in this, how do “mesenchymal stem cells” and “subepithelial cord derived mesenchymal stem cells” differ structurally/functionally?).
Further, the specification fails to describe or provide evidence of possessing a method comprising method step (b) alone and/or in combination with step(s) (a), (c), and/or (d). The claims as originally filed (claims set filed 07/15/2022) only recite method steps (a) obtaining a monocytic cell population, (b) culturing the monocytic cell population in media conditioned by regenerative cells, and optionally (c) “adding factors capable of supporting/synergizing with regenerative cells at inducing generation of inflammation suppressing myeloid cells”. None of the dependent claims further limited the method by obtaining a regenerative cell population (let alone a subepithelial umbilical derived mesenchymal stem cell population). The instant specification largely comprises recitations of “preferred methods include embodiments where…”, but do not ever clearly recite all the method steps of claim 1 together, nor provide a working example as claimed in claim 1. The working examples also described obtaining umbilical cord mesenchymal stem cells from umbilical cord samples [001082], but not specifically subepithelial umbilical cord mesenchymal stem cells.
United States Court of Appeals for the Federal Circuit, FWP IP APS v. Biogen MA, Inc (Case 2017-2109; decided October 24, 2018).
Piecing together elements of several claims and/or disparate portions of the specification to arrive at the specifically claimed subject matter does not satisfy the written description requirement. The task of locating the now-claimed subject matter within the original claims is made uncommonly more difficult by the original claims themselves, which are written in a cascading, multiple dependencies manner such that many of them generically refer back to any one of the preceding claims. Title 35 forbids this type of claim drafting because it can—as here—lead to bizarrely complex chains of cross-referencing claims in which one multiple dependent claim impermissibly serves as a basis for other multiple dependent claims. Finding the presently recited combination of specific experimental parameters, including the specific combination of disparate subgenus experimental parameters “in the morass of possible combinations of the impermissibly-drafted original claims would-- as Judge Learned Hand
observed in a different but related context—take “the patience of a yogi to decipher their meaning, as they stand.” Victor Talking Mach. Co. v. Thomas A. Edison, Inc., 229 F. 999, 1001 (2d Cir. 1916). A review of the claims and their intermixing dependencies presents an overall picture of a set of claims designed to preempt a conspicuously large number of different dosage regimens for a large variety of conditions using a long list of formulations, which is disconnected from a written description that is far more limited in its disclosure.
The disclosure of 63/223,245 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application.
Accordingly, the effective priority date of claims 1 and 13 of the instant application is granted as the effective filing date of the current application, July 15th, 2022.
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).
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Alternatively, if Applicant believes that support for claim 1 is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity, where such support may be found.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence. EP §2163.06 (I) last sentence.
Regarding claims 1 and 13, the concentration of interferon gamma and growth factor(s) are recited at a high level of generality, e.g., no positively recited concentration(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 recited functional language (i.e., creating conditioned media; inducing differentiation of cells).
The specification fails to disclose what structural changes to the method steps of claims 1 and 13 (e.g., interferon gamma, growth factor(s) concentration) is necessary and sufficient to produce conditioned medias (claim 1) and mesenchymal stem cells (claim 13) sharing the same functional properties, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
As discussed above, the specification provides no guidance or working examples for the method steps of claim 1, or the concentrations of interferon gamma or growth factor(s).
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.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc).
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)
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 and 13 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.
As discussed in the 112(a) rejection above, the method steps involving interferon gamma and growth factor(s) are recited at a high level of generality. If the presence of interferon gamma changes the conditioned media created in claim 1, and the presence of growth factors changes the structure/function of the mesenchymal stem cells produced in claim 13, then one has variable results depending on the working concentration(s). As written, it is unclear what conditioned media and mesenchymal stem cells are being produced. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Claim 13 recites “culturing single cells in the presence of at least one growth factor in an amount sufficient to induce the differentiation of said clusters of cells into mesenchymal stem cells”. The recitation of “an amount sufficient” in the claim denotes that not all amounts of growth factors are effective at inducing the differentiation of said clusters of cells into mesenchymal stem cells. What is the objective amount that is not ‘sufficient’, as opposed to the objective amount that is necessarily and predictably ‘sufficient’? The specification does not provide any guidance or teachings on what amount(s) are ‘sufficient’ for inducing the differentiation of said clusters of cells into mesenchymal stem cells.
A sufficient amount to induce differentiation is a dependent upon many different variable parameters, such as the growth factor present, type of stem cells, and the phenotypic response to be achieved. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
Claim Rejections - 35 USC § 112(d)
Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The recitation of “mesenchymal stem cells” in claim 13 is broader in scope than “subepithelial umbilical cord derived mesenchymal stem cells”, as recited in claim 1. Therefore, the recitation of “wherein said mesenchymal stem cells are generated from pluripotent stem cells by a) culturing single cells in the presence of at least one growth factor in an amount sufficient to induce the differentiation of said clusters of cells into mesenchymal stem cells; and b) adding one or more of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), bone morphogenic protein 4 (BMP-4), stem cell factor (SCF), Flt 3L (FL), thrombopoietin (TPO), EPO, and/or tPTD-HOXB4.” In claim 13 fails to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Monguio-Tortajada (Monguio-Tortajada, Marta, et al. "Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine." Theranostics 7.2 (2017): 270.) and further in view of Patel (Patel, Amit N., et al. "Mesenchymal stem cell population isolated from the subepithelial layer of umbilical cord tissue." Cell Transplantation 22.3 (2013): 513-519.- by Applicant).
Monguio-Tortajada teaches investigating the immunomodulatory of UC-MSC conditioned media on T cells and monocytes (Abstract).
Monguio-Tortajada teaches isolating monocytes using a MagniSort Human CD14 Positive Selection kit (pg. 282, “Monocyte polarization”, para 1). As previously stated in the 102 rejection in the Non-Final Office Action mailed 04/08/2024, it is well known in the art that interferon gamma receptor is expressed by most cells, including monocytes (e.g., see Elco and Sen cited in the Non-Final Office Action mailed 04/08/2024). As such, absent evidence to the contrary, one of ordinary skill would conclude that the monocytes isolated by Monguio-Tortajada express IFN-gamma receptor, and use methods well known in the art to also isolate cells based on expression of IFN-gamma receptor.
The UC-MSCs taught by Monguio-Tortajada were seeded in bovine EV-depleted culture medium with or without 200 ng/ml (120 IU/ml) IFNγ. Supernatant was then collected and centrifuged to exclude cells and cell debris, resulting in a primed UC-MSC conditioned medium. In some cases, USCMSC-EVs were also isolated from the conditioned medium (pg. 280-281, “EV isolation”).
After culturing monocytes under different conditions (including conditioned medium created from IFN-gamma primed UC-MSCs), Monguio-Tortajada found that UCMSC-EVs do not affect CD80, CD163 and CD206 polarization marker expression in monocytes, while the non-EV fraction and conditioned medium induce increased expression of CD163 and CD206 (Figure 7).
Monguio-Tortajada does not teach the MSCs being derived from subepithelial umbilical cord. The UC-MSCs taught by Monguio-Tortajada were isolated by sectioning umbilical cord into 3-6 mm^3 pieces, then carefully washed in PBS to eliminate residual blood contained in arteries and vein. During mechanical disruption, elimination of UC vein and subendothelium was achieved (pg. 280, “UC collection, MSC isolation, culture and characterization”.
Patel teaches isolating MSCs from the subepithelial layer of umbilical cord tissue. To do so, umbilical cords were dissected and the artery, veins, and Wharton’s jelly were removed, leaving the subepithelial layer (pg. 514, “Umbilical Cord Tissue Processing”).
Patel characterizes this cell population using functional assays, noting that unlike other MSC populations derived from umbilical cord, subepithelial UC-MSCs do not express STRO-1 (pg. 513, col 2, para 2). Compared to other isolated MSC-like cells from the umbilical cord, cells isolated from the subepithelial layer have a higher proliferation capacity (Fig. 2) and lower levels of Lin and HLA-ABC (pg. 519, col 1, para 1). These cells were similar to other MSCs in that that were positive for CD9, SSEA4, CD44, CD90, CD166, CD73, and CD146 (Fig. 4), but negative for hematopoietic markers CD14, CD34, and CD45 (pg. 518, col 1, para 1).
Patel also teaches collecting the culture medium from the subepithelial UC-MSCs cell culture to isolate exosomes (pg. 515, “Exosome Isolation”).
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute the UC-MSCs, as taught by Monguio-Tortajada, with the sUC-MSCs taught by Patel, in a method of generating a monocytic lineage cell capable of suppressing inflammation and inducing activation of endogenous regenerative cells with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Additionally, one would have a reasonable expectation of success because both UC-MSCs taught by Monguio-Tortajada and sUC-MSCs taught by Patel are derived from umbilical cord tissue, and as taught by Patel, share similar properties (e.g., both secrete exosomes (comparable to EVs in Monguio-Tortajada), express CD90, CD166, CD73, negative for CD14, CD34, CD45, etc.) (Patel- pg. 518, col 1, para 1; Monguio-Tortajada- pg. 271, “UCMSCs characterization”). Absent evidence to the contrary, the functional differences noted between UC-MSCs and subepithelial UC-MSCs (e.g., subepithelial UC-MSCs express STRO-1, other UC-MSCs do not) would not render the subepithelial UC-MSCs unusable in the method taught by Monguio-Tortajada.
M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
An artisan would be motivated to substitute the UC-MSCs with sUC-MSCs in a method of generating a monocytic lineage cell capable of suppressing inflammation and inducing activation of endogenous regenerative cells because Patel teaches that sUC-MSCs have lower levels of HLA-ABC compared to other umbilical cord-derived MSCs, and HLA-ABC expression can be problematic for allogeneic cell-based therapies. Patel also teaches that it was previously known that the immunosuppressive properties of MSCs make the cells a good candidate for potential allogeneic uses and treatment for acute graft-versus-host disease (pg. 513, col 1, para 1). As such, the lower expression of HLA-ABCs in sUC-MSCs makes them a more suitable candidate for allogeneic cell-based therapies (pg. 519, col 1, para 1).
Additionally, one would be motivated to use the sUC-MSCs in a method of generating a monocytic cell capable of suppressing inflammation because the sUC-MSCs cells can be cultured for greater than 90 population doublings with no indication of senescence, changes in morphology, or changes in their multilineage potential. Additionally, Patel characterized immunosuppressive properties of the sUC-MSCs, such as secreting exosomes (i.e., microvesicles) (pg. 518, “Discussion”), while Monguio-Tortajada demonstrates that nanosized EVs (extracellular vesicles, comparable to exosomes/microvesicles) retain the immunosuppressive effect of MSCs mainly by inhibiting T cell proliferation and preventing the secretion of pro-inflammatory cytokines by polyclonally stimulated T cells (pg. 271, col 2, paras 1-2).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Monguio-Tortajada and Patel and further in view of Lian (Lian, Qizhou, et al. "Directed differentiation of human-induced pluripotent stem cells to mesenchymal stem cells." Mesenchymal Stem Cells: Methods and Protocols (2016): 289-298.).
Neither Monguio-Tortajada nor Patel teach generating MSCs from pluripotent stem cells (iPSCs) by a) culturing single cells in the presence of at least one growth factor in an amount sufficient to induce the differentiation of said clusters of cells into mesenchymal stem cells; and b) adding one or more of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), bone morphogenic protein 4 (BMP-4), stem cell factor (SCF), Flt 3L (FL), thrombopoietin (TPO), EPO, and/or tPTD-HOXB4.
Lian teaches a protocol for differentiating iPSCs into MSCs. In the protocol, differentiating iPSCs were trypsinized into a single cell and cultured with supplements including bFGF. The single cell-based MSC-like colonies were then identified and expanded for the establishment of MSC lines in 15–20 days (pg. 290, para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to combine the methods of Monguio-Tortajada and Patel with Lian by generating MSCs via the method taught by Lian to then be used in the method(s) taught by Monguio-Tortajada and Patel. One would have a reasonable expectation for success because MSCs cells generated with the protocol taught by Lian express typical MSCs surface markers and undergo adipogenesis, osteogenesis, and chondrogenesis similar to adult bone marrow-derived MSCs (BM-MSCs), WJ-MSCs, and sUC-MSCs, and therefore would not impact the outcome/active methods steps of the method(s) of Monguio-Tortajada and Patel. One would be motivated to make this combination because as taught by Lian, MSCs generated from differentiated iPSCs display a higher proliferative capacity, up to 120 passages, without obvious loss of self-renewal potential and constitutively express MSCs surface antigens (Abstract).
Response to Arguments
The Applicant has filed a Declaration (Patel; 07.07.2025). The Examiner acknowledges and has considered the Patel Declaration filed under 37 CFR §1.132 on 7/07/2025 (see further discussion below).
In response to the 112(a) rejection regarding the claim language “capable of”, the Applicant submits in the Remarks filed 07/07/2025 that the functional property recited in claim 1 “capable of suppression of inflammation and activation of endogenous regenerative cells” is inherent to the steps/structures of claim 1. As such, the examiner notes that any art that discloses/teaches the same steps/structure of the claims will be interpreted as also being capable of suppression of inflammation and activation of endogenous regenerative cells, even if not explicitly stated in the art referenced.
Applicant's arguments filed 07/07/2025 regarding the specification as filed failing to teach more than one agent have been fully considered but they are not persuasive. Although the claim is argument is directed to is canceled (claim 21), similar logic is applied to the 112(a) rejection of claims 1 and 13 above.
The recitations cited by the Applicant for support (e.g., [0751-0752] – “products”) are generic and do not provide enough support for the claimed invention. For example, the term “products”, is a generic term that can read on a vast number of structures. How would one know what is considered a product vs. not? Additionally, the recitation of “comprising” or “at least one” does not lead an artisan to conclude specifically what two growth factor(s), markers, etc. can be used together, nor show possession of the claimed invention. As stated above, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species (i.e., just because the specification lists CD14 and IFN-gamma receptor as two different species/embodiments/options for positive selection does not mean Applicant has possession of using both CD14 and IFN-gamma together).
Applicant’s arguments with respect to Tokhanbigli and Romieu-Mourez have been considered but are moot because the new ground of rejection does not rely on these references for any teaching or matter specifically challenged in the argument.
In response to applicant's argument that the claimed invention achieves results that would have been unforeseen and surprising to a person skilled in the art, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The statements by Patel in the Declaration were not found to be persuasive. First, the study discussed in the Patel declaration (also filed by Applicant 07/07/2025, titled “Perinatal MSC Secretome Licensing Directs Monocyte Polarization Toward Immunomodulatory Lineage with Enhanced Regenerative Efficacy”) used umbilical cord, bone marrow, and adipose derived MSCs. MSCs were licensed with 10ng/ml IFN-gamma for 48 hours.
The declaration discloses that UC-MSC conditioned media “uniquely drives potent M2 polarization and regenerative outcomes… supporting the superiority of perinatal MSC-derived secretome” (pg. 12 of arguments). This result was also found in the teachings of the Patel 2013 reference cited in the 103 rejection above. Further, Mrahleh, also cited in the 103 rejection above, used WJ-MSCs, which are derived from the umbilical cord and are considered perinatal MSCs, and demonstrated upregulation of IL-10 and TGFB1 in monocytes, for example (Table 5) (i.e., the study included with the Patel Declaration also showed this result).
In addition, other prior art such as DeWitte (De Witte, Samantha FH, et al. "Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease." Stem Cell Research & Therapy 8.1 (2017): 140.) teach treating UC-MSCs with 50ng/ml IFN-gamma for 3 days. The number of UC-MSC expressing the negative costimulatory molecule PD-L1 increased with IFN-γ and MC treatment, compared to untreated UC-MSC (Table 1; pg. 6, col 1, para 2) (Patel’s declaration also discloses UC-MSC-CM increasing PD-L1 expression- “Summary Results” of study filed with declaration). Therefore, the results of the claimed invention are not found to be unexpected or surprising.
Additionally, there is no recitation of subepithelial umbilical cord-derived MSCs. As such, it is unclear how to results of the study pertain to the claimed invention since the claimed method comprises a different MSC population (i.e., would one expect the same results as the UC-MSCs taught? If so, then how do subepithelial UC-MSCs differ from UC-MSCs?).
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/KEVIN K HILL/ Primary Examiner, Art Unit 1638