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 .
Upon further consideration additional rejections are needed. As such, the instant office action is a non-final office action.
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 51-65 and 72 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
Claims 51 and 72 recite, “mortal pluripotent stem cells”. The specification does not provide an explicit definition for this term. Thus the term must be given its common art-accepted understanding of the term. By definition a pluripotent stem cell is one that self-renews indefinitely. As such, they are immortal cells. Thus, it is not apparent how a pluripotent cell can be immortal, given that if the cell has a finite doubling capacity, the cell does not meet the definition of pluripotent. Thus, the metes and bounds of the claimed cell are not apparent because “mortal” and “pluripotent stem cell” is contradictory.
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 51-65 and 72 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.
When determining if a recited genus has adequate written description for a genus:
(1) the broadest reasonable interpretation of the genus is determined;
(2) the disclosure is examined to determine if the specification has provided a representative number of species to describe the complete structure of the genus;
(3) the disclosure is examined to determine whether a representative number of species have been sufficiently described by other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus; and
(4) the state of the art is examined to the determine if it supports/supplement the genus description in the specification in a manner that would demonstrate the application was in possession of the claimed genus at the time of effectively filing.
Genus: “a population of isolated mortal pluripotent stem cells (MPSCs)”
Breadth of the Genus: The it is a cell considered to be “mortal” meaning a finite life-span. The cell is also described as “pluripotent” meaning that it has the ability to self-renew indefinitely, gives rise to all cells types of the three germ layers of the embryonic body, form chimeric embryos, and express at least Oct-4. As discussed above it is not apparent how a cell can be pluripotent and mortal. As such, breadth of the term genus is a cell that immortal and/or mortal and has at least one known characteristics of pluripotency. The cell is further recite as having “at least 89 doublings”. The breadth of this genus cell encompasses cells that only have 89 doubles but can have any number more, including indefinite numbers of doublings. As such, the cell can be mortal and immortal simultaneously. The breadth of “pluripotent stem cell” means it can be an induced pluripotent stem cell, one isolated from an embryo, or one isolated from any other part of the body. The claim does not specify the species of origin, so it can be from any organism that can comprise a “mortal pluripotent stem cell”.
Specification Description:
[0019] Disclosed herein are novel unique mortal pluripotent stem cells (MPSCs) produced in vitro, compositions thereof, and uses thereof in generating differentiated cells of various phenotypes (e.g., pancreatic, neural, hepatic, immunoregulatory, or natural killer cell phenotype) or treating disorders (e.g., diabetes, neural loss or degeneration, liver diseases, cancers, inflammations, viral infections, or autoimmune diseases) or improving conditions (e.g., skin conditions). The MPSCs are distinct from previous trophoblast stem cells and have advantages including but not limited to: fast and scalable population doublings; demonstrated pathogen-free profile; being highly immune privileged and suitable for transplantation; having exceptional chromosomal stability, for example possessing stable karyotype at least to 71 population doublings; and producing robust secretome rich with cytokine, chemokines, and exosomes. The MPSCs are distinct from embryonic stem cells, and are ethically sourced and cultured. Although the MPSCs are mortal (e.g., having definite proliferation capacities), they are capable of reaching population doubling much faster than embryonic stem cells and iPS cells. Unlike the cells from placenta, umbilical cord, or bone marrow, the MPSCs are pluripotent and capable of differentiating or maturing into three primary group of cells that form a human being: ectoderm (giving rising to the skin, neurons, and nervous system), endoderm (forming the gastrointestinal and respiratory tracts, endocrine glands, liver or hepatocyte-like cells, and pancreas or pancreatic cells), and mesoderm (forming bone (osteocytes), adipose, cartilage (chondrocytes), most of the circulatory system, muscles, connective tissue, immune cells, and more). Furthermore, the MPSCs are non-tumorigenic, e.g., not inducing tumor or teratoma, as demonstrated in the studies of immune competent rats.
[0061] In some cases, a non-embryonic mammalian stem cell (e.g., a trophoblast stem cell) can be a source cell to make mortal pluripotent stem cells (MPSCs) disclosed herein. In some instances, the mammalian stem cells are isolated from amniotic fluid, amniotic membrane, Wharton's jelly, chorionic villi, or ectopic pregnancy, in a manner that is not disturbing nor destructive to an embryo.
[0084] MPSCs expressed a variety of cell biomarkers, including β-hCG, HLA-G, heat shock protein 90 (HSP90), and CDX2 immunocytochemically (FIG. 5A). However, MPSCs did not express proliferation marker Ki-67, HSP70, tumor suppressor p53, and cell-cell fusion protein Syncytin (FIG. 5B), supporting the concept that MPSCs stand at the first position of TE-differentiated trophoblasts. Specifically, MPSCs expressed HLA-A,B,C and surface and intracellular HLA-G by flow cytometry analysis (FACS) using different antibodies (FIG. 5C; FIG. 5D). However, they did not express HLA-DR.
[0086] Human MPSCs Exhibit Immune Cell-Associated Biomarkers. The cells were characterized with immunocytochemistry and FACS analysis. The results showed that MPSCs expressed a variety of biomarkers associated with immune cells, including: cluster of differentiation (CD)56, CD16.sup.dim, inhibitory receptor KIR2DL4, CD11b, activating receptor NKp46, and CD10 of NK cells (FIG. 6A); TCR, CD49f, ILT-4, CD3, CD4, CD8, CD44, CD90/Thy-1, CD44, and CD166 of T cells (FIG. 6B); CD19 and CD141 of dendritic cells (FIGS. 6C and 6D); CD14 of macrophages (FIG. 6E); Flt3L (FIG. 6F) and CD34 of hematopoietic stem cells (FIG. 6G); and CD38 of lymphocytes (FIG. 6G). Subsequently, the expression of those biomarkers in MPSCs was analyzed with 8 independent cell lines, showing a similar pattern of NK and T cell biomarkers, wherein (CD16+CD56).sup.+ cells and CD107(+) cells showed the highest expression in the MPSCs. Biomarkers of NK cells and T cells occupy the most immune cells in MPSCs ,while CD107(+)CD(16+56)(+) cells and CD8(+)CD(16+56)(+) cells occupied the most cell populations in MPSCs by FACS analysis.
Thus specification describes one human species of cell that expresses HLA-A,B,C and G, Hsp90, and immune cell marker ITL4 among others, have a high but finite doubling population and rate as compared to embryonic stem cells. The only characteristic of “pluripotent stem cell” that the cell comprises is the ability to differentiate into the three embryonic germ layers and lineage cells therefrom. The cells specification discloses that this one species of cell does not have any other characteristics of pluripotency, and are in fact “mortal”. As such, the cell while having one characteristics of being pluripotency, appear to be more akin to an adult stem cells than a pluripotent cell.
State of the Art: The art established definition of a pluripotent stem cells is not that has the ability to self-renew indefinitely, differentiates the three embryonic germ cells and thus all cell type of the body proper, have the capacity to contribute to chimeric embryos, and express pluripotency marker, most significantly Oct4 (Romito and Cobellis. Stem Cell International 2016 pp. 1-20).
Gregori et al (Front. Immunol 6:128.pp. 1-8, 2015; of record) teach human EVT cells that express HLA-G, Hsp90, but is silent as to the expression of other HLA markers. Gregori also teaches their EVT cells do not express ITR4 and are silent has to any characteristics of pluripotency. Gregori also teaches an additional cell type in close association and interaction with EVT in vivo which are CD10 cells with are immunological cells also expressing HLA-G and ITR4. See table 1. CD10 cells are also known to express HLA-A, B, C and Hsp90 which are all the structural limitations of the claimed cell. However, they are described in the art as terminally differentiated cells without the ability to self-renew.
Both these cell types seem to be the closest cell types described in the art to those described in the instant application. The art definitely defines pluripotent cell stem as one that are immortal, not mortal, express pluripotency markers, form teratomas, have the capacity to contribute to chimeric embryos, and differentiate into cells of the three embryonic germ layers.
Therefore, the instantly claimed genus of “mortal pluripotent stem cells” is not adequately described by the specification. The specification describes one species of a type of stem cell that is mortal and has one characteristic in common with a pluripotent stem cells and has more characteristics of an immune cell. The breadth of the term “mortal pluripotent stem cell”, as the understanding of the term can be ascertained is much broader than the one species. As such, the specification does not provide a describes of a representative number of species of the genus, “mortal pluripotent stem cells” to adequately describe the complete structure of the genus. Further, the art teaches that the claimed cell does not fit the definition and description of being a pluripotent stem cell because it lacks most of the characteristics that define a pluripotent stem cell. As such, given the specification does not provide adequate description of the complete structure of the genus “a mortal pluripotent stem cell” and it is contradictory to the art accepted understanding of “mortal” cells and “pluripotent stem cells”, an artisan would have difficulty envisioning what the genus “a mortal pluripotent stem cell” and would conclude that they were not in possession of the genus or even a cell that can be described as both mortal and pluripotent. As such, the genus “a mortal pluripotent stem cell” lacks adequate written description.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 51-65 and 72, as amended, previously presented and newly added, are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more.
The claim(s) recite(s) “a population of mortal pluripotent stem cells”.
According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e. process, machine, manufacture, or composition of matter). Claims 51-65 drawn to a composition of matter comprising a population of cells. Thus claims 51-65 meet the requirements for step 1 of the analysis.
Second, the claim is assessed to determine if it is directed to a judicial exception under step 2A. Under 2019PEG, “directed to” is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application”, requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful limitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 2106.05 for examples of integration of practical application).
Regarding the first prong (1), claims 51-65 are expressly directed to “a population of mortal pluripotent stem cells (MSCP). The specification teaches a non-embryonic mammalian stem cell (e.g., a trophoblast stem cell) can be a source cell to make mortal pluripotent stem cells (MPSCs) disclosed herein. In some instances, the mammalian stem cells are isolated from amniotic fluid, amniotic membrane, Wharton's jelly, chorionic villi, or ectopic pregnancy, in a manner that is not disturbing nor destructive to an embryo ([0061]). Thus the claimed population of cells are found within blastocysts (trophoblast cells), amniotic fluid, amniotic membrane, Wharton’s jelly, and chorionic villi, which are all products of nature. Thus the claimed cells are also products of nature.
Regarding the second prong (2), the claimed product does not recite any limitations that would be considered integration into a practical application. Thus, claims 51-65 meet the requirement of step 2A as being directed to a judicial exception.
Third, if a judicial exception is present in the claim, it is further assessed to determine if the claim recites any additional elements or steps that are sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception. Claim 51 recite the population of cells with the additional elements of having the functional characteristics of being “mortal”, “pluripotent” and the functional/structural characteristics of expressing markers HLA-G and HSP90, with at least 80% having HLA markers A, B, and C. The claims also recite the additional functional limitations at least 89 population doubling times within about 90 days from a start of culturing the MSPCs. All of these element solely describe structural/functional inherent to the cell and not any particular modification to the cell. As such, the claimed cell population encompasses one that is present in its source cell or isolated therefrom. Therefore, the claimed population of cell is not marked different in any way from its natural counterpart.
Regarding dependent claims 53-65, all of these claims further specify marker expression and chromosomal quality that are inherent to the cell present within the natural counterpart. As such, these claims also do not markedly distinguish the population of cells from their natural counterpart.
As such, claims 51-65 do not meet the requirements of step 2B of the 2019PEG because the cell population is not markedly different from its natural counterpart.
In conclusion, claims 51-65 do not meet all the requirements of the 2019PEG and therefore are deemed patent ineligible.
Response to Arguments
Applicant's arguments filed 9/23/2026 have been fully considered but they are not persuasive.
Applicant refers to MPEP 2106.04(c)(II)(C) provides that when evaluating characteristics to determine whether they are “markedly different”, the claimed product must “possess at least one characteristic that is different from that of the counterpart”. Applicant submits that at least four markers that different between Gregori’s EVTs and the claimed cells. On this basis alone the claimed MPSCs exceed the required threshold of at least one characteristic.
In response, Applicant is not considering MPEP 2106.04(c)(II)(C) in full. MPEP 2106.04(c)(II)(C) states, “The courts have emphasized that to show a marked difference, a characteristic must be changed compared to nature, and cannot be an inherent or innate characteristic of the occurring counterpart”. Examiner has contended that the difference in marker expression is an inherent response to a change in culture conditions. The previous office actions have provided evidence from Applicant’s own disclosure that the culturing culture conditions alter phenotypic responses by MPSC cells. Applicant has not provided evidence that the MPSC cells outside of environmental changes have a transformative marked distinction outside of inherent or innate characteristics of the occurring counterpart. As such, consistent with MPEP 2106.04(c)(II)(C), the claimed MSCP population continues to be deemed a judicial exception.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
