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 .
Applicant’s amendment and response filed on 5/18/2026 has been received and entered into the case.
Claims 27-32 are newly added, claims 1-18 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 19-32 have been considered on the merits. All arguments have been considered.
Response to Amendment
The claim rejection under 35 USC 101 has been withdrawn due to the instant amendment.
The declaration under 37 CFR 1.132 filed 5/18/2026 is insufficient to overcome the rejection of claims 19-26 as set forth in the last Office action.
The declaration discussed and presented data to support the conclusion that the claimed invention was able to “reduce batch-to-batch variability” and “lower allosensitization risk” by pooling step of MSCs from multiple donors, and provide suitability for “off-the-shelf” use of the MSCs in treating conditions like type 1 diabetes.
It is acknowledged that Ta et al. disclose a step of further culturing the pooled MSCs from the multiple donors before administering according to Example 1. However, the pooled MSCs are known to be used directly without further culturing according to Ardanaz et al. and thus, it would have been obvious to a person skilled in the art to use the WCB of Ta et al., i.e. pooled WJ-MSCs, without further culturing prior to administering. The declaration stated that the WCB of Ta et al. cannot be considered a pharmaceutical composition which is directly administrable to a patient based on the definitions in the document. It is understood that the difference between the final composition of Ta et al. and the claimed composition is whether the culturing of MSCs to achieve a certain concentration (e.g. 25-200 million cells) is carried out prior to the pooling or after pooling. Ta et al. teach additional culturing after pooling in order to obtain the desired amount whereas the claimed invention requires pooling of sufficiently expanded donor MSCs without further culturing. While the difference is acknowledged. However, as the pooling without further culturing prior to the administration is known in the art, it is obvious to a person skilled in the art to use the MCB of Ta et al. which can comprise 1-5 million cells to make WCB, i.e. pooled MSCs, and used them for the method of treating autoimmune disease, particularly in the absence of any unexpected results derived from not having further culturing as claimed. The declaration showed evidence that the claimed pooled MSCs have reduced variability. However, reduced variability is due to the pooling per se and there is no evidence that this is due to the without further culturing after pooling and before administering as claimed. Furthermore, Ta et al. discuss that pooling from multiple donors diminishes intra-sample variability (p.25). Furthermore, the data shown for low allosensitization risk in the declaration does not provide any evidence whether or not this is due to the without further culturing after pooling. Rather it is understood that an immediate use of cryopreserved pooled cells would minimize allosensitization.
The alleged exceptional therapeutic potential discussed in the declaration in view of other studies is a mere comparison between the claimed composition (ProTrans) and a placebo group. There is no evidence that the alleged outcome is due to the “without further culturing after pooling and prior to administering” as claimed.
In the absence of clear evidence that the claimed feature of not further culturing after pooling and prior to the administration provides unexpected results of the claimed method in treating a condition compared to the method of Ta et al. which further culturing after pooling prior to the administration, it is the Examiner’s position that the combined teaching of Ta et al. in view of Ardanaz et al. would render the claimed method obvious along with cited references.
Claim Rejections - 35 USC § 112 (New Rejection)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 19-32 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.
The instant claims are directed to a method of treating or preventing a condition by administering pooled MSCs selected based on the claimed assay steps, and the condition includes inflammatory disease, autoimmune disease and transplantation rejection.
The term “treating” is not particularly defined in the instant specification, and thus, the scope of the term “treating” is broadly interpreted as a plain meaning of the term known in the art. Thus, the “treating” would encompass preventing, alleviating, improving, and also curing. Under this interpretation, the scope of “treating” would include “curing” of any condition belonging to inflammatory disease, autoimmune disease and transplantation rejection. The claims also disclose the term “preventing” and this scope is also encompassed by the term “treating”. Therefore, it is reasonable to conclude that the scope of the claimed method would encompass “preventing”, “alleviating or improving” and “curing” any inflammatory disease, any autoimmune disease and transplantation rejection.
The specification fails to provide sufficient written description supporting the above-identified scope of the claimed invention. The instant specification does not provide any Examples or working embodiment to support that the claimed “prevention” or “cure” for the inflammatory disease, autoimmune disease and transplantation rejection.
The instant specification indeed discussed the MSCs’ capacity to promote survival, angiogenesis and tissue repair and modulate responses by innate and adaptive immune cells citing Berman et al. (2010, Diabetes) (para. 3). The specification also discloses that Maintenance of residual insulin secretion is important in contributing to lower HbA1c, less blood glucose fluctuations, and diminished risk of ketoacidosis, and it also substantially decreases the risks of severe hypoglycemic events and late complications. The specification provides a prediction that an identified successful intervention may not only be used to prevent disease but also be applied to patients with ongoing disease before overt hyperglycemia, thereby providing means to prevent disease development (para. 4). There is no disclosure in the instant specification that the MSCs pooled as claimed would be able to achieve “prevention” and/or “cure” of any known inflammatory disease, autoimmune disease and transplantation rejection.
The use of MSCs for various therapeutic applications is well known in the art. However, there is no known evidence that any MSCs would be able to prevent any inflammatory disease, autoimmune disease and transplantation rejection.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Clarification is required. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”
M.P.E.P. § 2163 also recites, “An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention… one must define a compound by ‘whatever characteristics sufficiently distinguish it’. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.” And further, “The description needed to satisfy the requirements of 35 U.S.C. 112 “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d at 1357, 76 USPQ2d at 1084.< Patents and printed publications in the art should be relied upon to determine whether an art is mature and what the level of knowledge and skill is in the art. In most technologies which are mature, and wherein the knowledge and level of skill in the art is high, a written description question should not be raised for claims >present in the application when originally filed,< even if the specification discloses only a method of making the invention and the function of the invention. See, e.g., In re Hayes Microcomputer Products, Inc. Patent Litigation, 982 F.2d 1527, 1534-35, 25 USPQ2d 1241, 1246 (Fed. Clarification is required. 1992) (“One skilled in the art would know how to program a microprocessor to perform the necessary steps described in the specification. Thus, an inventor is not required to describe every detail of his invention. An applicant’s disclosure obligation varies according to the art to which the invention pertains. Disclosing a microprocessor capable of performing certain functions is sufficient to satisfy the requirement of section 112, first paragraph, when one skilled in the relevant art would understand what is intended and know how to carry it out.”). In contrast, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.”
In the absence of any disclosure supporting the claimed scope, and lack of knowledge in the art that MSCs would be able to prevent or cure any inflammatory disease, autoimmune disease and transplantation rejection, it is considered that the applicant did not have possession for the claimed invention.
Scope of Enablement Rejection
Claims 19-32 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 alleviating, improving the symptoms of inflammatory disease, autoimmune disease or transplantation rejection, does not reasonably provide enablement for preventing or curing the claimed condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The instant claims are directed to a method of treating or preventing a condition by administering pooled MSCs selected based on the claimed assay steps, and the condition includes inflammatory disease, autoimmune disease and transplantation rejection.
The term “treating” is not particularly defined in the instant specification, and thus, the scope of the term “treating” is broadly interpreted as a plain meaning of the term known in the art. Thus, the “treating” would encompass preventing, alleviating, improving, suppressing and also curing. Under this interpretation, the scope of “treating” would include “curing” of any condition belonging to inflammatory disease, autoimmune disease and transplantation rejection. The claims also disclose the term “preventing” and this scope is also encompassed by the term “treating”. Therefore, it is reasonable to conclude that the scope of the claimed method would encompass “preventing”, “alleviating or improving” and “curing” any inflammatory disease, any autoimmune disease and transplantation rejection.
The scope of inflammatory disease would include those listed in the instant specification (see para. 78) as well as claims 27-30 which would also include autoimmune disease and transplantation rejection (graft rejection) as well as GVHD. Claim 30 is particularly directed to type 1 diabetes or latent autoimmune diabetes in the adult (LADA).
As discussed above in the written description rejection, the instant specification does not provide any working example or guidance how any of the claimed condition would be prevented or cured by the pooled MSCs produced by the claimed method. For example, many autoimmune diseases cannot be prevented or cured (see p.2 and 5-6, Autoimmune disease – Boston Children’s Hospital, 2026). While MSCs’ immunosuppressive property would provide some treatment for autoimmune diseases, however, it is not known at the time of filing that prevention or cure of any autoimmune diseases by MSCs is achievable.
M.P.E.P. § 2164.03 reads, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The ‘amount of guidance or direction’ refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) (“In applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required.”).”
Regarding the specific example of type 1 diabetes or LADA (claims 30-32), the instant specification discloses prophylactic example (Example 8) without any showing of the claimed pooled MSCs would prevent or cure type 1 diabetes. Jayashinghe et al. (2022, Cureus) teach that mesenchymal stem cells (MSCs) are a highly promising novel treatment for T1D and their discovery has advanced biological sciences by allowing for modification of cell fate and the development of higher-order cellular structures (Abstract). However, the review article of Jayashinghe et al. does not provide any evidence that MSCs would be able to prevent or cure T1D. Kashbour et al. (2025, Diabetol. Metab. Syndro.) summarize clinical trials using MSCs to treat type 1 and 2 diabetes mellitus and concluded that there are some effects of MSCs in treating T1DM and T2DM, however, there is no indication of preventing or curing these diseases.
Cleveland clinic (2024) teaches that there's no way to prevent LADA diabetes, because you can't control or prevent the autoimmune condition that causes it and there's no cure for Type 1.5 diabetes (p.3).
The level of one of ordinary skill in the art at the time of invention was advanced, being that of a person holding a Ph.D. or an M.D.; however, because of the immaturity of the art, and its unpredictability with prevention and/or cure of inflammatory diseases, particularly autoimmune diseases, as shown by the other factors, one of skill in the art at the time of invention by Applicant would not have been able to make and/or use the invention claimed, to its fully-claimed scope, without undue experimentation.
The court has recognized that physiological activity is unpredictable. In re Fisher, 166 USPQ 18 (CCPA 1970). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved. In re Fisher, 166 USPQ 18 (CCPA 1970).
It is not to be left up to the skilled artisan to figure out how to make the necessary starting materials and then to figure out how to use them to produce the biological effects as recited in the claims. The courts held that the disclosure of an application shall inform those skilled in the art how to use applicant's claimed invention, not how to find out how to use it for themselves. In re Gardner et al. 166 USPQ 138 (CCPA 1970). For the broad scope of the claims, this specification only teaches what is intended to be done and how it is intended to work, but does not actually teach how to do that which is intended.
Given the limited working examples, the limited guidance provided in the specification, the broad scope of the claims with regard to the outcome of the claimed method, and the unpredictability for preventing and/or curing inflammatory disease, autoimmune disease or transplantation rejection, undue experimentation would have been required for one skilled in the art to practice the claimed methods of preventing or curing the inflammatory disease, autoimmune disease and transplantation rejection.
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 19-32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 discloses a new limitation directed to a step of administering the pharmaceutical composition to said patient without further culturing the isolated, pooled allogeneic MSC population after pooling and prior to said administering. It is not clear what the “pharmaceutical composition” is referring to. It is not clear if the “pharmaceutical composition” being administered is the pharmaceutical composition prepared by the combining step or the cryopreserved pharmaceutical composition. It appears that the administering step would use the cryopreserved composition but the step does not clearly disclose if the pharmaceutical composition administered is required to be cryopreserved prior to the administration (i.e. thawing step is required). Clarification is required. Applicant is advised to amend the administering step, for example, “administering the cryopreserved pharmaceutical composition after thawing to said patient without further culturing…”
Claim 28 discloses that the transplantation rejection comprises organ transplant, hematopoietic stem cell transplantation, cell transplantation and islet transplant. It is not clear how the transplantation rejection can be transplantation itself or transplant. It appears that the limitation is not properly stated. Clarification is required.
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) 19, 21-27 and 29-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. (WO2012/131618) in view of Ardanaz et al. (2016, BMC Veterinary Research), Deskins et al. (2013, Stem Cells Translational Medicine) in further view of Francois et al. (2011, Molecular Therapy), Solchaga et al. (2012, Am. J. Stem Cell), Killer et al. (2017, Stem Cell Research & Therapy), Solomon et al. (2018, Biol. Blood Marrow Transplant.; published on 1/17/2018), and Klinker et al. (2017, PNAS)
Regarding claim 19 and 25-26, Ta et al. teach a method of isolating, culturing and pooled allogeneic Wharton’s jelly-derived mesenchymal cell population from multiple donors (Abstract). Ta et al. teach that Wharton’s jelly derived MSCs (WJ-MSCs) from each individual are culturing and passaged and Master Cell Bank (MCB) of each individual umbilical cord is established, and pooling is from plurality of established MCB to establish a Working Cell Bank (WCB), and both MCB and WCB are cryopreserved in cryopreservation composition for further use or used directly (p.8, lines 16-31; p.15, lines 6-12). Ta et al. exemplified 5 individual samples (Fig. 1), which would meet the limitation of claim 26.
Regarding the intended purpose of the claimed method being for treating a condition comprising inflammatory disease, autoimmune disease or transplantation rejection, Ta et al. teach that the allogeneic composition comprising of pooled WJ-MSC is for therapeutic use and more specifically for managing autoimmune disorders (p.14, last sentence).
Regarding “at least 3 individual donors” of claim 19, Ta et al. exemplified 5 individual samples and pooled (Fig. 1) and Example 1 shows 3 individual donors. Regarding the MSCs having at most been subject to eight passages, Ta et al. teach that MCB is established at P1 (p.19, lines 21-23).
Regarding the number of MSCs derived from any one donor does not exceed 50% of the total cell number (claim 19), Ta et al. teach that equal number of MSCs from each cord is pooled to form a single working cell bank (p.20, lines 1-2). Considering that the pooled MSCs of Ta et al. are from “multiple” donors including 3 individual donors or 5 individual donors as discussed above, the number of cells from each donor would not inherently exceed 50% of the total cell number when pooled.
Regarding the step of assaying each individual donor derived MSC population using at least 3 assays to obtain at least 3 assay results for each individual donor derived MSC population, allocating individual ranking score value to individual donor derived MSC population, allocating a total score value based on the at least 3 assay results, and selecting a subset with desirable population properties based on the total score values for pooling, Ta et al. do not teach the limitation.
Ardanaz et al. teach a method of preparing pooled allogeneic BM-MSCs for treating musculoskeletal injuries (Abstract; Method at p.6, 2nd col. “Study design”), and Ardanaz et al. teach a step of characterizing BM-MSCs prior to pooling to optimize the treatment (Fig. 1). Ardanaz et al. teach that allogeneic MSCs provide the possibility to be selected according to their characteristics to optimize the treatment (higher immunomodulatory capacity, rate of growth in culture, etc.) (p.2, Background, 1st col., 3rd para.).
Deskins et al. teach that in order to maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used, and such prediction of MSC potency can be made by feasible and reproducible in vitro assays (Abstract). Deskins et al. teach the use of scoring system for the MSC properties from the assay analyzing various different donors/cell lines for engraftment in a mouse wound model, and MSCs with higher scores for in vitro tests show higher engraftment and vascularity (see Fig. 5).
It would have been obvious to a person skilled in the art to carry out quality analyses on MSCs from multiple donors in order to obtain MSCs with highest quality measured by assays for immunomodulatory properties prior to pooling the allogeneic MSCs from multiple donors taught by Ardanaz et al. and Deskins et al. for the method of Ta et al. This is because Ardanaz et al. teach a step of characterizing BM-MSCs prior to pooling to optimize the treatment and Deskins et al. teach that the prediction of their therapeutic abilities of MSCs by in vitro assay to determine their properties would allow the best cells used in clinical applications in order to maximize efficacy of MSCs.
Ta et al. in view of Ardanaz et al. and Deskins et al. do not particularly teach the characterization includes the assay measuring IDO, PGE2 and the effect of the MSCs on proliferation of PBMCs.
Francois et al. teach that there are discrepancies in the immunosuppressive capacity of MSCs, and such variability in the immunosuppressive potential of each MSC donor source can be measured by IFN-mediated IDS upregulation, and IDO activity is correlated with the immunosuppressive capacity of MSCs (seen entire document).
Solchaga et al. teach that PGE2 measured from a conditioned medium of hMSCs is a putative potency indicator of the immunosuppressive activity of hMSCs (see entire document).
Killer et al. teach that co-culture of MSCs with PBMC in an allogeneic T-cell proliferation assay would measure the potency of immunosuppressive function of the MSCs (Abstract; Conclusion).
It would have been obvious to a person skilled in the art to carry out the assays measuring IDO, PGE2 and proliferation of PBMC as taught by Francois et al., Solchaga et al., and Killer et al., respectively, to determine the immunosuppressive capacity of the MSCs from each donors to select the optimal MSCs for the therapeutic application with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because it is known in the art that there are variabilities in MSC’s immunosuppressive properties as taught by Francois et al., and the assay determining immunosuppressive capacity would allow one skilled in the art to choose the best MSCs as intended by Deskins et al.
Regarding the ranking score value from each individual assay on the donor MSCs, and the total score value based on the at least 3 individual ranking score value from the at least 3 assays (claim 19), Ta et al. in view of Ardanaz et al. and Deskins et al. do not particularly teach the limitation.
However, the use of scoring system to identify and select the best candidate is well known in the art.
Solomon et al. teach the use of a donor selection scoring system based on the various donor characteristics, variables on a certain outcome (p.792, 2nd col., last para.; Table 4). According to Table 4, each donor is given with a score for each variable, and the best donor to optimize survival or relapse reduction is chosen with highest score from the added up points (i.e. total score).
Klinker et al. teach a method of determining immunosuppression scores for various sources of MSC for stimulated and unstimulated condition (Fig. 6). Klinker et al. developed their own method of scoring immunosuppression utilizing AUC value based on morphology of MSCs, and higher AUC values represent weaker immunosuppression (p. E2600).
Thus, it would have been obvious to one skilled in the art to generate a donor selection scoring system similar to that of Solomon et al. or Klinker et al. for selecting the best donor MSCs having the higher immunosuppressive capacity using the assay results from determining immunosuppressive capacity of MSCs by measuring IDO, PGE2 and proliferation of PBMS taught by Francois et al., Solchaga et al. and Killer et al. for each donor with a reasonable expectation of success.
Regarding the MSCs having at most been subject to eight passages (claim 19) or 2-6 passages (claim 24), Ta et al. teach that MCB is established at P1 (p.19, lines 21-23). Furthermore, Ta et al. teach WJ-MSCs at passage 2 (P2/P3) can be used for as therapeutic composition (p.20, lines 8-10). Furthermore, Ardanaz et al. teach that approximately 106 cells from passage three were thawed and plated in a flask for three days and used on the different injections (p.7, 1st col., 1st para.). These teachings would meet the limitations of claims 19 and 24.
Regarding the step of combining the therapeutically effective amount of isolated, pooled allogeneic MSC population and a pharmaceutically acceptable excipient or carrier to make a pharmaceutical composition, Ta et al. teach that the carrier such as Plasmalyte A and HBSS for the final composition (i.e. pooled WJ-MSCs) (Table 2 at p.22). Furthermore, Ardanaz et al. teach that the injection of pooled allogeneic BM-MSCs is diluted in 3 ml of lactated ringer’s solution (LRS) (Method at p.6, 2nd col. “Study design”). The injection, i.e. pharmaceutical composition, of Ardanaz et al. is considered to be made by combining the pooled allogeneic MSCs with LRS, a pharmaceutically acceptable carrier/excipient.
Regarding the therapeutically effective amount of the isolated, pooled allogeneic MSC population, the amount is considered as any amount because the dosage is not particularly limited in the administering step for the intended purpose.
Regarding the step of cryopreserving after pooling, Ta et al. teach that a Working Cell Bank (WCB) established from polling MSCs from plurality of established Master Cell Bank (MCB), and the WCB is cryopreserved in a cryopreservation medium to obtain WCB composition (p.8, lines 25-31). Thus, the cryopreserved WCB composition of Ta et al. would meet the limitation.
Regarding the step of administering the pooled allogeneic MSC population without further culturing after the pooling step and prior to the administering, Ta et al. teach that the cells harvested at the WCB stage can be further cultured to generate therapeutic composition and cryopreserved (p.21). Considering that this teaching requires additional culturing after pooling, Ta et al. do not teach the claimed limitation of “without further culturing the MSC population after pooling and prior to the administering”.
Ardanaz et al. teach that the injection of pooled allogeneic BM-MSCs is diluted in 3 ml of lactated ringer’s solution (LRS) (Method at p.6, 2nd col. “Study design”). The injection, i.e. pharmaceutical composition, of Ardanaz et al. is considered to be made by combining the pooled allogeneic MSCs with LRS, a pharmaceutically acceptable carrier/excipient.
It would have been obvious to a person skilled in the art to use the WCB, i.e. pooled WJ-MSCs of Ta et al. directly without further culturing for the desired purpose of treating autoimmune diseases. A person of ordinary skilled in the art would have been motivated to do so because Ardanaz et al. teach that MSCs from multiple donors would be pooled and directly used for administration. Thus, administering WCB of Ta et al. without further culturing as taught by Ardanaz et al. would be obvious to a person skilled in the art in the absence of any unexpected results.
It is noted that Ta et al. teach that the WCB as well as the final pharmaceutical composition can be cryopreserved. Thus, it is obvious that the cryopreserved WCB cryopreserved is thawed and administered to treat autoimmune diseases including T1DM.
Regarding claim 21, the limitation is directed to the number of assayed MSCs from individual donors being at least one more than those pooled in the pooling step. While the combined teachings of the cited reference above do not particularly teach the limitation, however, it would have been obvious to a person skilled in the art that the screening assays of IDO, PGE2, and PBMC proliferation inhibition leading to the ranking of each individual MSCs would result in either all of the MSCs would meet the criteria (number of assayed = number of pooled), some of the tested/assayed MSCs would meet the criteria (number of assayed > number of pooled), or none of the tested/assayed MSCs would meet the criteria (number of pooled = 0). Based on these possibilities, the last one would not be considered as the method requires pooling MSCs. Then, the possibilities from the selection would be either the numbers are the same or the number of pooled would be smaller than the number of assayed. Considering the variability of MSCs from different donors, it is expected that the number of pooled would be smaller than the number of MSCs assayed.
Regarding claim 22 directed to the number of assayed donor MSCs being at least 2-4 times as many as the number of pooled, the same analysis can be applicable as above. The number of pooled donors would be determined by how stringent the threshold for the results to select MSCs for pooling of Ta et al. in view of Ardanaz et al. and Deskins et al. Therefore, the ratio of assayed vs. pooled would be routinely optimizable by changing the stringency of the selecting candidates from the assays.
Regarding claim 23 directed to the number of MSCs (cell concentration) of each donor not being exceed 4 times of the number of cells of other donors in the pool, while the combined teachings of the references do not particularly teach the limitation, however, the number of cells from each donor in the pool of the pooled MSCs of Ta et al. would be modified based on the amount of cells obtained from each donor. For example, if the MSCs from each donor are combined at the equal number per donor, then the claimed limitation would be met. As the pooling of MSCs taught by Ta et al. is intended to reduce variability of the cells from different donors (p.25, lines 20-22), one skilled in the art would not use MSCs from a single donor dominate the whole pooled population in their number, and by doing so, the claimed limitation would be met. This would also meet the requirement of the claims directed to any one donor does not exceed 50% of the total cell number.
Regarding claims 27, 29-30 directed to the type 1 diabetes (T1D), Ta et al. teach the immune-mediated injury in autoimmune diseases can be type 1 diabetes (p.32, claim 19).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 20 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. in view of Ardanaz et al. and Deskins et al. in further view of Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al. as applied to claim 19 above, and further in view of Rizzo et al. (2008, Cytotherapy; of record)
Regarding claim 20 directed to an assay measuring HLA-G expression in the MSCs in response to IL-10, the cited references do not teach an assay measuring HLA-G expression in MSCs in response to IFN- or IL-10.
However, it is known in the art that soluble HLA-G antigens play a role in immune modulation mediated by MSCs according to Rizzo et al. Rizzo et al. teach that IL-10 is one of the main up-modulators of soluble HLA-G, and exogenous IL-10 induced sHLA-G molecule secretion by MSC along (Abstract: Results).
It would have been obvious to a person skilled in the art to assay the secretion of sHLA-G by MSCs by IL-10 as one way to determine immunomodulatory property of MSCs along with IDO and PGE2 discussed above. One skilled in the art would recognize that the determining the value of the sHLA-G secreted by MSCs would be in addition to IDO, PGE2, PBMC proliferation inhibition of MSCs to determine that the MSCs from individual donors to select the best candidate for pooling in the method of Ta et al. in view of Ardanaz et al. and Deskins et al. with a reasonable expectation of success. These factors are all known parameters of immunomodulatory properties of MSCs, and thus, it would have been obvious to combine them together to determine the immunosuppressive property of the MSCs.
Regarding claim 28 directed to the transplantation rejection comprising GVHD, the cited references do not particularly teach the limitation.
Rizzo et al. teach that co-transplantation of autologous bone marrow mesenchymal stromal cells and hematopoietic stem cells may enhance engraftment, reduce the severity of GVHD and improve clinical outcome in autoimmune diseases (introduction at p.364).
It would have been obvious to a person skilled in the art to use the pooled MSCs of Ta et al. in view of Ardanaz et al. and Deskins et al. for GVHD as MSCs are known to have immunosuppressive properties to reduce severity of GVHD according to Rizzo et al.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 31-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. in view of Ardanaz et al. and Deskins et al. in further view of Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al. as applied to claim 30 above, and further in view of Hu et al. (2013, Endocrine Journal)
Regarding claim 31 directed to the patient having T1D diagnosed no more than 3 years, Ta et al. in view of Ardanaz et al. and Deskins et al. in further view of Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al. do not teach the limitation.
Hu et al. teach that WJ-MSCs from umbilical cord is for newly-onset type 1 diabetes mellitus, and that if newly diagnosed T1DM patients can be treated with adequate insulin injections to relief the hyperglycemic toxicity on islet, they might have a “honeymoons” during which they may maintain a good glycemic control with a little or no insulin injections, but this period is usually not longer than 1.5 years (p.355).
It would have been obvious to a person skilled in the art to use the pooled WJ-MSCs of Ta et al. in view of Ardanaz et al. and Deskins et al. in further view of Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al. to treat a newly diagnosed T1D patient that is no longer than 1.5 years based on the teaching of Hu et al. with a reasonable expectation of success.
Regarding claim 32 directed to the patient diagnosed with T1D has a fasting plasma C-peptide concentration of >0.01 nmol/L, Hu et al. teach that fifteen T1DM patients with fasting C-peptide >0.3 ng/mL was enrolled in the treatment, and this concentration can be converted to 0.1 nmol/L (0.3 ng/mL x 0.331 = 0.0993 nmol/L). Thus, the patient diagnosed with T1DM of Hu et al. meets the claimed limitation.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Double Patenting Rejection
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 19-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-7, 14, 21, 23 of copending Application No. 17/634,436 (reference application) in view of Ta et al. (supra), Rizzo et al. (supra) and Hu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘436 application disclose a method of obtaining an isolated, pooled allogeneic MSC population using at least 3 assays, any one donor not exceeding 50% of the total cell number, and the 3 assays include measuring IDO activity, PGE2 secretion, and measuring proliferation of PBMC, and at least one of the at least 3 assays being MSCs effect on T cells to suppress an immune response, etc., and the selection is based on the scoring system allocated to the results of each assay and the total score value being used for the selection. These are the same method steps disclosed in the claims of the instant application. The type of MSCs of the ‘436 application includes WJ-MSCs as the instant application.
Regarding the step of cryopreserving the isolated, pooled allogeneic MSC population of the instant application (claim 19), the claims of the ‘436 application do not teach the limitation. However, it would have been obvious to a person skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘436 application for the future use with a reasonable expectation of success. One skilled in the art would recognize that cryopreservation is a well-known option for storing cells regardless they are pooled or not, and thus, it is considered a well-known option to a person skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘436 application after pooling for the storage purpose with a reasonable expectation of success. For example, cryopreserving pooled allogeneic MSCs is known in the art as taught by Ta et al. Ta et al. teach that Master Cell Bank (MCB) of individual MSCs is optionally cryopreserving the MCB, and then pooling the [thawed] MCB to establish Working Cell Bank (WCB), and optionally cryopreserving the WCB (p.8, lines 24-31). Thus, it would have been obvious to one skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘436 application.
Regarding HLA-G expression of claim 20 of the instant application, the claims of the ‘436 application do not teach the limitation. However, it is well known in the art that soluble HLA-G antigens play a role in immune modulation mediated by MSCs according to Rizzo et al. Rizzo et al. teach that IL-10 is one of the main up-modulators of soluble HLA-G, and exogenous IL-10 induced sHLA-G molecule secretion by MSC along (Abstract: Results). As the assays of the ‘436 application are directed to measuring the immunosuppressive properties/potentials of MSCs, and Rizzo et al. teach that HLA-G secreted by MSCs upon IL-10 is involved in the immunomodulatory potential of MSCs, one skilled in the art would try to measure HLA-G expression/secretion by MSCs as additional property of MSCs having immunosuppressive properties for the pooling.
Regarding the combining step of the isolated, pooled, allogeneic MSC population with a pharmaceutically acceptable carrier to make a pharmaceutical composition, claims 21 and 23 of the ‘436 application disclose that the isolated, pooled allogeneic MSC population is a part of the pharmaceutical composition and further contains a pharmaceutically acceptable carrier. Regarding the therapeutically effective amount, claim 14 of the ‘436 application discloses a method of using the isolated, pooled, allogeneic MSC population being administered at a therapeutically effective amount. Thus, it would have been obvious to a person skilled in the art to use a therapeutically effective amount of the isolated, pooled, allogeneic MSC population in the pharmaceutical composition with a reasonable expectation of success.
Regarding claim 21, the limitation is directed to the number of assayed MSCs from individual donors being at least one more than those pooled in the pooling step. While the combined teachings of the cited reference above do not particularly teach the limitation, however, it would have been obvious to a person skilled in the art that the screening assays of IDO, PGE2, PBMC proliferation inhibition, and HLA-G leading to the ranking of each individual MSCs would result in either all of the MSCs would meet the criteria (number of assayed = number of pooled), some of the tested/assayed MSCs would meet the criteria (number of assayed > number of pooled), or none of the tested/assayed MSCs would meet the criteria (number of pooled = 0). Based on these possibilities, the last one would not be considered as the method requires pooling MSCs. Then, the possibilities from the selection would be either the numbers are the same or the number of pooled would be smaller than the number of assayed.
Regarding claim 22 directed to the number of assayed donor MSCs being at least 2-4 times as many as the number of pooled, the same analysis can be applicable as above. One skilled in the art would expect that the number of pooled donors selected from the total number of assayed donors would be determined by the desired stringency or threshold of the selection of MSCs for pooling. Therefore, the ratio of assayed vs. pooled would be routinely optimizable by changing the stringency/threshold of the selection resulted from the assays.
Regarding claim 23 directed to the number of MSCs (cell concentration) of each donor not being exceed 4 times of the number of cells of other donors in the pool, while the combined teachings of the references do not particularly teach the limitation, however, the number of cells from each donor in the pool of the pooled MSCs of the ‘436 application would be modified based on the amount of cells obtained from each donor. For example, if the MSCs from each donor are combined at the equal number per donor, then the claimed limitation would be met.
Regarding claims 27 and 29 directed to T1DM, the claims of the ‘436 teach autoimmune disease, and it is well known in the art that T1DM is one of many known autoimmune diseases.
Regarding claim 31, Hu et al. teach that WJ-MSCs from umbilical cord is for newly-onset type 1 diabetes mellitus, and that if newly diagnosed T1DM patients can be treated with adequate insulin injections to relief the hyperglycemic toxicity on islet, they might have a “honeymoons” during which they may maintain a good glycemic control with a little or no insulin injections, but this period is usually not longer than 1.5 years (p.355).
Regarding claim 32 directed to the patient diagnosed with T1D has a fasting plasma C-peptide concentration of >0.01 nmol/L, Hu et al. teach that fifteen T1DM patients with fasting C-peptide >0.3 ng/mL was enrolled in the treatment, and this concentration can be converted to 0.1 nmol/L (0.3 ng/mL x 0.331 = 0.0993 nmol/L). Thus, the patient diagnosed with T1DM of Hu et al. meets the claimed limitation.
Thus, the claims of the ‘436 application in view of Ta et al., Rizzo et al. and Hu et al. render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Regarding the 101 rejection, applicant’s arguments with respect to the instant amendment have been fully considered and are persuasive. The 101 rejection has been withdrawn.
Regarding the 103 rejection, applicant argues that the WCB of Ta et al. is a manufacturing intermediate not a pharmaceutical composition for direct administration. It is acknowledged that the WCB of Ta et al. is further cultured to prepare the final composition for therapeutic purpose. However, there is no evidence that WCB cannot be directly used for any therapeutic application. The difference between the WCB and the final composition is whether they are expanded after pooling. This does not teach away of using WCB for a therapeutic purpose. As discussed the claim rejection above, based on the teaching Ardanaz et al., the individual MSCs are pooled and used directly after pooling. Thus, one skilled in the art would apply this concept to use the WCBs of Ta et al. for administering directly without further expansion with a reasonable expectation of success and in the absence of any evidence that the claimed feature of not further culturing after pooling provides any unexpected results. As discussed above, the declaration filed does not provide any evidence supporting that the “without further culturing after pooling and prior to the administration”
Applicant argued that Ta does not teach assay-based donor ranking or subset selection. It is acknowledged that Ta does not teach the claimed assay, however, as discussed in the claim rejection, the claimed assay system has been addressed based on the teachings of Deskins et al., Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al.
Applicant alleged that Ta’s quantitative composition constraints are not taught stating that “equal number of MSCs from each cord” is an incidental example, not a claimed requirement. The Examiner respectfully disagrees with this allegation. Not only Ta teaches the use of equal number of MSCs from each donor but Ardanaz et al. also teach the same quantity (5 million cells) of cells pooled to obtain 25 million total cells.
Applicant mentioned selection of donors based on a scoring algorithm that controls the ration of maximum 4:1 between any two donors. The instant claims do not require these limitations, and yet the equal number of cells being pooled from each donor as taught by Ardanaz et al. would meet the limitation. Regarding the <8 passages, the combined teachings of Ta and Ardanaz would not further culture after pooling and thus, the Ta’s WCB would meet the limitation.
Applicant argued that Ardanaz does not cure the Ta’s deficiency, and alleged that Ardanaz does not teach selection or exclusion as it teaches pooling of all available donors. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant’s argument with regard to Deskins et al., Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al. is also attacking the reference individually when the rejection is based on the combinations of references.
Applicant alleged that Solomon and Klinker are not analogous art. In response to applicant's argument based on non-analogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
Applicant argued that the combination lacks motivation and reasonable expectation of success. The Examiner disagrees with this allegation. As discussed in the claim rejection, pooling MSCs from individual donors is known in the art, and various references cited in the claim rejection reasonably arrives the claimed assay system to select the best donors for the therapeutic purpose. The difference of Ta et al. and the claimed invention appears to be the presence or absence of post-pooling culturing/expanding as Ta teaches a step of further expanding after pooling, i.e. WCB composition, to make a final composition. However, this key difference is considered obvious based on the teaching of Ardanaz et al. in the absence of evidence showing that this omission of further culturing/expanding renders the claimed invention and the produced pooled MSCs provide unexpected results. It is expected that the pooled MSCs with or without post-pooling expansion/culturing would be the similarly effective in treating the claimed condition. This is because there is no reason to believe that the manipulation of additional expansion after pooling would change the properties of the MSCs.
For the double patenting rejections, the rejection based on the ‘436 application has been modified to address the amendment. The rejection based on the ‘507 application has been withdrawn due to the instant amendment. Applicant has requested to hold the rejections in abeyance. The rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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