DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-8) in the reply filed on May 8, 2026 is acknowledged.
Claims 9-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The examiner apologizes for the oversight on sending a second restriction, dated May 29, 2026). The restriction dated May 29, 2026 is hereby WITHDRAWN; the only restriction of record is the dated May 8, 2026.
Claims 1-15 are presented in the most recent claim set, dated May 8, 2026. Claims 5,6, 13 and 15 have been amended. Claims 9-15 are withdrawn. Elected claims 1-8 are examined below.
Priority
The present application is a continuation of the International Application No. PCT/IB2025/060979, filed Oct. 28, 2025. Applicant’s claim for the benefit of a prior-filed parent provisional applications 63/712,907 and 63/748617, filed Oct. 28, 2024 and Jan. 23, 2025, respectively, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is Oct. 28, 2024.
Information Disclosure Statement
The information disclosure statement filed May 8, 2026 is in compliance with the provisions of 37 CFR 1.97 and the size fee assertion was filed under 37 CFR 1.17(v). Accordingly, the IDS has been considered by the examiner.
Claim Rejections - 35 USC § 112
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 5-7 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 inclusion of 10 mM TCA in the culture medium, does not reasonably provide enablement for any bile acid (claim 5), specific bile acids – GCA, GCDCA, TCDCA, GDCA, TDCA, TαMCA, and TUDCA (claim 6) or solely TCA (claim 7). 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.
To be enabling, the specification of the patent application must teach
those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561(Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of
experimentation is permissible, if it is merely routine, or if the
specification in question provides a reasonable amount of guidance
with respect to the direction in which experimentation should
proceed to enable the determination of how to practice a desired
embodiment of the claimed invention.
PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
1As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
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 provided,
7) the presence or absence of working examples,
8) the quantity of experimentation necessary
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833,839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1) The nature of the invention and 2) the breadth of the claims
The claims are drawn to a method of generating adipose-derived stromal cells (ASCs) from adipose-tissue including the steps of providing a cell preparation derived from adipose tissue and a culture medium including about 0.5-50 ng/mL VEGF; 0.5-50 ng/mL EGF; about 1-100 ng/mL bFGF; about 2-200 ng/mL IGF; about 0.1-10 µg/mL ascorbic acid and about 0.02-2 µg/mL hydrocortisone and any bile acid (claim 5); specific bile acids – GCA, GCDCA, TCDCA, GDCA, TDCA, TαMCA, and TUDCA (claim 6) or solely TCA (claim 7). Thus, the claims taken together with the specification imply that Applicant is claiming that any bile acid at any concentration will work in a cell culture medium to generate ASCs.
3) the state of the art, 4) unpredictability of the art and 5) the relative skill of those in the art
The relative skill of those in the art is high, generally that of a PhD in biochemistry or a research physician.
That factor is outweighed however by the unpredictable nature of the art. As taught by Sawitza et al. (Sci Rep, 2015), bile acids induce hepatic differentiation of mesenchymal stem cells. (Title). Specifically, 2 µM of bile acids GCDCA, TUDA, CA, GCDCA, TCA, TCDCA, and TLCA were used and promoted differentiation of bone marrow and umbilical cord MSCs from rodents and bone marrow MSCs from humans. TUDCA was found to be the most potent differentiation agent. TUDCA was tested at other concentrations – lower (0.5 µM and 1 µM) and higher (20 µM and 100 µM), which did not function as well for differentiation or resulted in cell death over time. (pg. 2, “Results”; pg. 3, Fig. 1).
B-H Cha et al. (Biomaterials, 2014) also investigated the role of TUDCA on in vitro differentiation of human adipose-derived stem cells (hASCs) into adipocytes, concluding that TUDCA decreased adipogenic differentiation of hASCs in vivo and in vitro (pg. 2852, 1st col., 1st full para.; pg. 2857, “Conclusions”). B-H Cha et al. incubated hASCs with 50, 100 and 150 µM TUDCA in proliferation medium for 3 days, finding TUDCA was not cytotoxic, cell proliferation increased gradually and the rate of proliferation was not significantly different at any concentration of TUDCA as compared to the control (no addition of TUDCA). (pg. 2853, “3.1 Viaiblity and proliferation of hASCs by TUDCA treatment”).
The specification teaches that the specific bile acid TCA present at 10 µM in conjunction with the 7 claimed factors can enhance proliferation of adipose-derived MSCs. (see paras. [0157], [0217], [0285]-[0286], Ex 4, Fig. 5A-E).
Thus, the person of ordinary skill in this art has an understanding that bile acids, particularly TUDCA at specific concentrations and administered at particular time points can play a role in differentiating adipose-derived MSCs. That person does not have an understanding of the role that any bile acid, even TUDCA, plays in proliferation of MSCs at any concentration, as B-H Cha et al. has concluded that TUDCA at various concentrations had no significant influence over proliferation of adipose-derived MSCs. This understanding would prompt a person of ordinary skill to conclude that different bile acids at different concentrations might play a role in differentiation of MSCs and that 10 µM of TCA can promote proliferation of adipose-derived MSCs when combined with the seven claimed factors in the particular circumstances detailed in the examples in the specification.
As Sawitza et al. explain, “…physiological concentrations of bile acids can trigger the differentiation of rodent and human MSC into hepatocyte-like cells in vitro, which involves the bile acid receptors Fxr and Tgr5 as well as several signaling pathways known to control stem cell development.” (pg. 2, 1st full para.)
There is no way for one skill in the art to know, a priori, that any bile acid at any concentration in conjunction with the seven claimed factors will promote proliferation with a reasonable expectation of results. Thus, the state of the prior art does not support the broad scope of the above claims.
6) the amount of direction and guidance provided and 7) the presence and absence of working examples
The specification teaches 10 µM of TCA can promote proliferation of adipose-derived MSCs when combined with the seven claimed factors in the particular circumstances detailed in the examples in the specification. The specification does not explain how any bile acid, at any concentration can be used in conjunction with the claimed circumstances to generate/proliferate adipose-derived MSCs.
Because of the general lack of information on the role of bile acids in proliferation of MSCs generally or adipose-derived MSCS specifically, there is no reasonable expectation that any bile acid at any concentration, or even TCA at any concentration will function in the claimed method; there is no support in the art for the role of bile acids in proliferation of MSCs; the art generally teaches that bile acids promote differentiation of MSCs (the opposite of proliferation); and the art further teaches that different bile acids work better for that than others. (TUDCA being the best, at least under the circumstances taught by Sawitza et al.); any bile acid at any concentration would not reasonably be expected to function as a MSC proliferation enhancer, as B-H Cha et al. explicitly teach that various concentrations of TUDCA had no effect on proliferation of adipose-derived MSCs, nor do applicants teach any other bile acid at any other concentration than 10 µM TCA.
8) The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept the assertion that any bile acid, at any concentration can be used in conjunction with the claimed seven factors to generate/proliferate adipose-derived MSCs as inferred in the claims and contemplated by the specification.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable." (42 USPQ 2d 1001, Fed. Circuit 1997).
To practice the invention of the instant claims requires undue experimentation due to unpredictability in the role of bile acids in proliferation of MSCs, their role in the differentiation of MSCs and the understanding that all bile acids do not function at the same level to promote differentiation and the lack of direction from Applicants’ disclosure regarding the same. The amount of experimentation required in order to proliferate MSCs with any bile acid at any concentration is extremely large due to the lack of evidence to support proliferation of MSCs by bile acids, the understanding that bile acids promote differentiation of MSCs and the evidence provided by B-H Cha et al. that suggests that bile acids do not promote proliferation of MSCs. To determine if any bile acid at any concentration would function to promote proliferation of MSCs when combined in a medium with the seven factors would require inventive effort and extensive experimental burden.
In light of the above discussion, the instant claims do not comply with the enablement requirement of 35 U.S.C. § 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Hong In Sun et al. (KR 20180045289, cited in IDS filed on May 8, 2026).
The claims are directed to methods for generating adipose-derived stromal cells (ASCs) from adipose-tissue including the steps of providing a cell preparation derived from adipose tissue and a culture medium including about 0.5-50 ng/mL VEGF; 0.5-50 ng/mL EGF; about 1-100 ng/mL bFGF; about 2-200 ng/mL IGF; about 0.1-10 µg/mL ascorbic acid and about 0.02-2 µg/mL hydrocortisone.
Hong In Sun et al. teach in vitro long-term culture of adult mesenchymal stem cells in a culture medium that maintains their proliferation and differentiation capabilities. (paras. [0004], [0069]). More specifically, Hong In Sun et al. teach that the adult mesenchymal stem cells can be adipose derived; (“ADSC”) (para. [0020], Ex. 2); and that the specific culture medium components include VEGF (2-100 ng/mL), EGF (2-100 ng/mL), bFGF (2-100 ng/mL), IGF (2-100 ng/mL), ascorbic acid (1-50 µg/mL), and hydrocortisone (2-100 ng/mL). (para. [0016], claim 2).
With respect to the independent claim, Hon In Sun et al. teaches overlapping ranges:
COMPONENT
CLAIMED
Hong In Sun et al.
VEGF
about 0.5-50 ng/mL
2-100 ng/mL
EGF
about 0.5-50 ng/mL
2-100 ng/mL
bFGF
about 1-100 ng/mL
2-100 ng/mL
IGF
about 2-200 ng/mL
2-100 ng/mL
Ascorbic acid
about 0.1-10 µg/mL
1-50 µg/mL
hydrocortisone
about 0.02-2 µg/mL
2-100 ng/mL
Hon In Sun et al. further teach that these seven growth factors (VEGF, EGF, bFGF, IGF, ascorbic acid and hydrocortisone) added separately to the culture medium did not have a significant effect on the proliferation of stem cells, but when combined at various concentrations, they increased proliferation of stem cells (including human adipose-derived mesenchymal stem cells) by 2-3 times as compared to without the combination of the seven. (para. [0039]).
With respect to claim 1, Hon In Sun et al. teach the claimed method of generating ASCs, with concentrations of all the factors that overlap with those claimed. “In the case where the claimed ranges, ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).” MPEP 2144.05.
With respect to claim 2, Hon In Sun et al. teach enriching the MSCs from the adipose tissue. (Ex. 2, paras. [0026]-[0028]).
With respect to claims 3 and 8, Hon In Sun et al. teach that optimizing of the cell culture medium for expansion of stem cells is essential, as stem cells are expected to be useful for treating intractable diseases. As it is currently understood that the factors secreted by stem cells are therapeutically valuable, and perhaps collecting these from stem cells and administering them as therapeutic agents may be more beneficial than administering the stem cells themselves, it would have been obvious to have enriched factors or extracellular vesicles released from the ASCs. The MSC would have been expected to have increased expression of angiogenic or neurogenic factors as Hon In Sun et al. teach providing the cell culture medium with the factors in overlapping ranges with those claimed, so this result should inherently flow from culturing the cells in the medium taught by Hon In Sun et al.
With respect to claim 4, Hon In Sun et al. teach that optimizing the concentrations for administration of the seven factors in the stem cells medium increased proliferation by 2-3 times that without the seven factors. It therefore, would have been obvious to have further optimized the concentrations within the ranges of those taught by Hon In Sun for VEGF, EGF, bFGF, IGF, and ascorbic acid. With respect to hydrocortisone, it would have been obvious to lower the concentration to determine if a lower amount would work the same as a higher amount, thereby using the smallest amount possible and providing a cost-savings over long-term production.
Conclusion
No claims are allowed.
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/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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