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 II (claims 3-13) in the reply filed on 5/26/2026 is acknowledged.
After further consideration, Group I invention claims (claims 1-2) have been rejoined along with Group II claims.
Claims 14-16 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-13 have been considered on the merits.
Claim Objections
Claim 1 is objected to because of the following informalities: the term “passing through” in step (d), 2nd line, appears to be more appropriate as “passed through”, instead.
Claim 3 is objected to because of the following informalities: the terms “HGF” and “MMP-1” appear for the first time in the claim and they would be appropriate as a full name followed by the abbreviation in a parenthesis.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-13 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.
Claim 1 discloses the step (a) of preparing human pluripotent stem cells (hPSCs) cultured to passage 70 or lower after establishing of cell lines. It is not clear if the cell lines established are of hPSCs or any other type of cells. If the cell lines are derived from the hPSCs, applicant is advised to amend the limitation accordingly. For search purpose, the limitation is interpreted as establishment of hPSC lines.
Claim 1 discloses the step (d) directed to isolating only monolayer-shaped cell clusters from the mesenchymal-like stem cells passing through the cell-permeable 3D culture unit. The “mesenchymal-like stem cells” in step (d) appears to refer the mesenchymal-like stem cell in step (c). It is not clear if the step (c) requires isolating mesenchymal-like stem cells from the cystic embryoid bodies loaded on the 3D culture unit. If mesenchymal-like stem cells are isolated in the step (c), it is not clear how the step (d) is carried out. Are there two isolating steps, i.e. step (c) and (d)?
It appears that step (c) is not the step for isolating mesenchymal-like stem cells. Rather those cells passing through the 3D culture unit from the cystic embryoid bodies loaded onto the 3D culture unit appear to form a monolayer-shaped cell cluster on the other side (i.e. bottom) of the 3D culture unit, and step (d) is directed to isolating those cells passed through the 3D culture unit. Clarification is required.
Claim 1 discloses that the mesenchymal-like stem cells express CD90 and SOX2 at a level of 95% or greater. It is not clear what the percentage is based on. Is this directed to a 95% or greater of mesenchymal-like stem cells in a population (e.g. each uniformized cluster of step (e)) express CD90 and SOX2 or the mesenchymal-like stem cells obtained by the claimed method express CD90 and SOX2 at a level of 95% or greater compared to a standard level of CD90 and SOX2 in a standard cell? If the level of CD90 and SOX2 is compared to a standard level in a standard cell, there is no indication what the standard would be. Without knowing a specific level or number for CD90 and SOX2 or any specific cell type as a standard (e.g. MSCs produced by different method), one cannot determine the level of CD90 and SOX2 expressed in the mesenchymal-like stem cells of the instant claims would be 95% or greater. Clarification is required.
Claim 3 discloses a limitation directed to the method of claim 1. As claim 1 has been withdrawn from the consideration, it is not clear what the limitation intends to point out. Applicant is advised to clarify the claimed limitation without referring to the withdrawn claim.
Claim 3 discloses “express CD90 and SOX2 at a level of 95% or greater”. It is not clear what is the standard that the level of CD90 and SOX2 expression is compared. Is it compared to the bone marrow-derived mesenchymal stem cells or any other cells. Or is it meant that 95% or greater of the mesenchymal-like stem cells express CD90 and SOX2? Clarification is required. For search purpose, 95% or greater of the mesenchymal-like stem cells express CD90 and SOX2.
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 1-13 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.
The instant claims disclose the use of a cell-permeable three-dimensional culture unit without any particular structure of the unit other than it allows cells pass through. This would encompass an embodiment such that the cells are migrated through the 3D culture unit and then attach to a separate culture dish forming a monolayer.
The specification of the instant application provides a definition of the term “cell-permeable 3D culture unit” as a cell-permeable instrument (p.19, 2nd full para.). This definition is extremely broad to encompass any 3D culture unit with a pore size bigger than the diameter of cells. The specification provides an example for the cell-permeable 3D culture unit as a cell-permeable artificial insert, a 3D insert for cell culture or a mesh made of nylon or fibrous material, or it can be prepared by bioprinting technology using various materials as claimed in claim 2 (p. 19, full 3rd para.).
While the specification exemplifies a culture insert for the cell-permeable 3D culture unit, however, the scope of the 3D culture unit capable of cell permeability is extremely broad, and the passing encompassed in the instant claims encompasses both passive and active ways. For example, the step of isolating the mesenchymal-like stem cells could be carried out by centrifugation through a filter/insert having pores sufficient to allow the cells to pass through, and those passed through would be collected and cultured as a monolayer.
It appears that the instant invention relies on the property of mesenchymal-like cells migrating through the 3D culture unit, and forming a monolayer on the opposite side of the culture unit. However, the scope of the instant claims does not particularly disclose the structural feature required for such limitation. It appears that the cell-permeable 3D culture unit for the claimed invention requires to have two space (upper and bottom) divided by the unit, and should allow one to recover the cells formed on the other side of the 3D culture unit. Consistently, the examples of such 3D culture unit are a 3D culture insert which is understood to have a cell-permeable mesh or membrane, and also a mesh made of nylon or fibrous material. Thus, the specification does not provide sufficient written description for any other 3D culture unit which encompasses numerous different shapes and materials.
Furthermore, the claims do not exclude using other means for separating mesenchymal-like stem cells from the embryoid bodies. Particularly, step (c) of claim 1 discloses that the cystic embryoid bodies are loaded on a cell-permeable 3D culture unit to isolate mesenchymal-like stem cells therefrom. The definition given to the term “cell-permeable 3D culture unit” is a cell permeable instrument as discussed above. Thus, the scope of step (c) would encompass isolating mesenchymal-like stem cells by any means using the cell permeable instrument (e.g. centrifugation of dissociated cells through a filter, etc.), and then step (d) requires isolating those mesenchymal-like stem cells forming a monolayer-shaped cell clusters. There is no limitation to step (d) such that the isolation step is directed to the monolayer formed on the other side (bottom) of the culture unit as shown in Figure 1 of the instant application.
Therefore, the scope of the claimed invention is broader than those disclosed in the instant specification, which appears to direct any 3D culture unit that is capable of providing an access to the bottom side of the culture unit (e.g. a culture insert or a mesh), and thus it is determined that the instant specification fails to provide sufficient written description to provide support for the entire scope of the claimed invention.
Applicant is advised to disclose the structural limitation(s) to the cell-permeable 3D culture unit such that the step (d) of isolating only monolayer-shaped cell clusters formed with the cells passed through the 3D culture unit. For example, one can add “wherein the monolayer-shaped cell clusters are formed on the other side (or bottom) of the 3D culture unit after the cells passed through the culture unit” or define the 3D culture unit providing an upper portion and a bottom portion or limit the 3D culture unit as a cell culture insert or a mesh. Applicant is reminded not to add any new matter when claims are amended.
Claims 10-12 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 treating cancer (claim 10) or any disease/condition disclosed in claim 12, does not reasonably provide enablement for “preventing” a cancer or any disease/condition of claim 12. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The instant claims disclose that the therapeutic composition comprising the mesenchymal-like stem cells would necessarily and sufficiently “prevent” any cancer or any disease/condition listed in claim 12.
The instant specification does not provide sufficient guidance or working examples that the claimed mesenchymal-like stem cells would prevent any cancer or any one disease listed in the instant claim. The specification discloses the property of the claimed mesenchymal-like stem cells and they have enhanced anti-inflammatory effect and immunosuppression based on the expression of specific proteins involved in these mechanisms.
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to “preventing” cancer broadly is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. There is no known mesenchymal stem cells
The cancer treatment art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of cancers broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancer cells in a mammal, including a human subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
The claim is very broad and inclusive of cancer cells and tumors generally. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claim is directed. The claim is extremely broad due to the vast number of possible cancer types represented by the term “cancer cells.”
The specification does not enable any person skilled in the art to which it pertains (i.e. prevention of cancer) to make or use the invention commensurate in scope with the claims. The lack of adequate guidance from the specification or prior art with regard to the actual prevention of any cancers with the mesenchymal-like stem cells fails to rebut the presumption of unpredictability existent in this art. Applicants fail to provide the guidance and information required to ascertain which particular type of cancer the claimed anticancer agent will be effective against without resorting to undue experimentation.
Absent a reasonable a priori expectation of success for using any specific chemotherapeutic agent/combination to prevent any particular type of cancer, one skilled in the art would have to extensively test many various tumor types. Since each prospective embodiment, and indeed future embodiments as the art progresses, would have to be empirically tested, and those which initially failed tested further, an undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise.
The same argument can be applicable to the diseases/conditions listed in claim 12. The listed diseases/conditions in claim 12 are directed to those inflammatory and/or immune system and none of these species is disclosed in the instant specification such that mesenchymal-like stem cells can effectively prevent any one of them. Merely showing the anti-inflammatory efficacy and/or immunosuppressive property of mesenchymal-like stem cells does not provide enablement for the claimed “prevention” of the listed conditions.
The pharmaceutical art is highly unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to the therapeutic effects, whether or not the pharmaceutical composition comprising mesenchymal-like stem cells would be effective for preventing cancer or those conditions listed in claim 12.
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 unpredictability for preventing cancer or other inflammatory and/or immune diseases as claimed, undue experimentation would have been required for one skilled in the art to practice the intended purpose of the claimed product.
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 and 3-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hong et al. (2015, Tissue Engineering: Part C) in view of Pettinato et al. (2015, Stem Cells and Development; IDS ref.) in further view of Jager et al. (2016, Adv. Med. Sci.; IDS ref.) as evidenced by WiCell Product Information (2015, IDS ref.).
Hong et al. teach a method of isolating mesenchymal stem cells differentiated from human embryonic stem cells using a commercialized transwell cell culture insert having 8 m pore size (Abstract; Fig. 1). It is submitted that the culture insert of Hong et al. would meet the cell-permeable 3D cell culture unit since the insert would allow the cells to pass through the membrane and forming cells at the lower region of the insert (see Fig. 1B).
Hong et al. teach that EB is plated onto a transwell insert and after 5 days incubation, and the cells migrated to the lower compartment were gently scraped and subcultured, and the isolated cells are MSCs (p.323, Materials and Methods).
Hong et al. teach that the human ESCs are hESC line H9 (p.323, Materials and Methods). Hong et al. do not teach the hESC line H9 is cultured to passage 70 or lower. However, the hESC line H9 utilized by Hong et al. is a commercially available cell line from WiCell, and according to WiCell product information, the H9 cell line is passage 24 for the lot released on 3/10/2015 (see attached). Thus, it is expected that the H9 cell line utilized in Hong et al. is less than passage 70 as claimed since Hong et al. do not teach any passage of the H9 cell line.
Hong et al. do not teach a step of isolating cystic EBs.
However, it is known in the art that cystic EBs primarily comprised the endoderm lineage population according to Pettinato et al. (p.1596, 1st col.; p.1597, 2nd col.), and Pettinato et al. teach that cystic EBs have greater propensity toward endoderm lineages (p.1597, 2nd col.). Since the formation of mesenchymal stem cells from EBs derived from hESCs taught by Hong et al. is through EMT (p.328, Discussion), one skilled in the art would recognize that cystic EBs would be appropriate source for the EMT generating mesenchymal stem cells. Thus, it would have been obvious to a person skilled in the art to select cystic EBs for the method of Hong et al. with a reasonable expectation of success.
Hong et al. do not teach the step (e) of uniformizing the monolayer-shaped cell clusters to 100-500 m. However, it is well known in the art that cells harvested as a monolayer would be scraped off the surface and broken into smaller clusters by using a pipette tip. For example, Jager et al. teach a mechanical dissociation method using a pipette tip for the cells (p.3, 2.4. Mechanical Dissociation). Thus, it would have been obvious to a person skilled in the art to use a mechanical dissociation in order to subculture the mesenchymal stem cells of Hong et al. gently scraped from the lower compartment of the inserts with a reasonable expectation of success.
Regarding the longitudinal and transverse size of 100-500 m, it is submitted that mechanical dissociation or trituration using a pipette tip as taught by Jager et al. for the method of Hong et al. in view of Parenteau et al. would result into the claimed size of clusters. Jager et al. teach that 10 trituration with the P1000 pipette produced samples with a mean particle size of about 18172 m2 (Fig. 1). This size of the particle (about 18000 m2) taught by Jager et al. would be within the range of the claimed size would be in a range from 10000 m2 (100 m x 100 m) to 250000 m2 (500 m x 500 m), and thus, would meet the limitation.
Furthermore, the instant specification discloses that mechanical dissociation of the cells using a micropipette tip in order to prepare the clusters of the claimed dimensions (p.18, 2nd para.; p.30, last para.).
Regarding the mesenchymal-like stem cells of the instant claims express CD90 and SOX2 at the level of 95% or greater, the limitation is directed to the results obtainable from the claimed method. It is submitted that since the combined teachings of Hong et al. in view of Pettinato et al. in further view of Jager et al. disclose the method steps identical to the claimed steps comprising using cystic EBs which have greater propensity toward to endodermal lineage, isolating those migrated or passed through the culture insert, collecting the cells and culturing further, therefore, the combined teachings of the cited references would be able to produce the MSCs substantially similar, if not identical, to those claimed.
Regarding claim 3 directed to the mesenchymal-like stem cells prepared by the method of claim 1, the combined teachings of Hong et al. in view of Pettinato et al. and Jager et al. meet the method of making the mesenchymal-like stem cells, and thus, the mesenchymal-like stem cells resulting from the claimed method would be inherently produced by the method taught by the combined teachings of the cited references.
Regarding claims 4-9, the wherein clauses are directed to the characteristics of the claimed mesenchymal-like stem cells. As the mesenchymal stem cells produced by the method taught by Hong et al. in view of Pettinato et al. and Jager et al. are considered to be substantially similar, if not identical, to the claimed product prepared by the claimed method, the characteristics of the mesenchymal stem cells produced by the method of the combined teachings of the cited references would inherently meet the characteristics as claimed.
Regarding the therapeutic composition of claim 10 comprising a cellular therapeutic composition, the mesenchymal stem cells produced by the method of the combined teachings of the cited references are considered as a cellular therapeutic composition.
Regarding claim 11 directed to the therapeutic composition further comprising an active ingredient, Hong et al. in view of Pettinato et al. and Jager et al. do not particularly teach the limitation. However, it would have been obvious to a person skilled in the art to use additional therapeutically active ingredient for the purpose intended as Hong et al. teach that the hESCs-MSCs are used for therapeutic application for functional recovery of MI using a mice model of MI (p.328, 1st col.).
Regarding claim 12, the wherein clause of the claim is directed to the results a method of using the therapeutic composition, and it does not provide any structure to the claimed composition. Thus, the wherein clause does not provide any patentable weight in determining the product of the instant claims.
Regarding claim 13 directed to the transporter comprising the mesenchymal-like stem cells, the term “transporter” is interpreted broadly as any container that can carry the claimed cells, i.e. culture plates, dish, etc. Hong et al. teach the use of a transwell culture insert for culturing hESCs and isolating MSCs, and the isolated MSCs are cultured in a 60 mm dish (Fig. 1; p.323). The 60 mm dish taught by Hong et al. is considered to meet the claimed transporter comprising the mesenchymal-like stem cells of claim 13.
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 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hong et al. in view of Pettinato et al. and Jager et al. as applied to claims 1 and 3-13 above, and further in view of Parenteau et al. (US PAT. 5,374,515).
Regarding the 3D culture unit made of species as claimed in claim 2, Hong et al. do not teach the material for the porous membrane of the cell culture insert is any one of the claimed species.
However, it would have been obvious to a person skilled in the art to use any suitable material for the porous membrane having porosity of 8 m for the cell culture insert used in the method of Hong et al. with a reasonable expectation of success. For example, Parenteau et al. teach that a cell culture insert is made of polystyrene, polycarbonate, resin, polypropylene for walls of the cell culture insert with a porous membrane base of polycarbonate or other culture compatible porous membrane such as glass fiber or nylon, and the porosity of the membrane vary from 0.2 to 10 m (col. 5, lines 6-13). Thus, one skilled in the art would recognize that a cell culture insert can have walls made of polypropylene and a porous membrane made of glass fiber or nylon with the porosity of 8 m as taught by Parenteau et al. for the method of Hong 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.
Conclusion
No claim is allowed.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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