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 .
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 70-77 and 86, as amended or newly added, are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more.
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 70-77 are drawn to a composition of matter comprising a population of cells. Thus claims 70-77 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 70-77 are directed to a population of undifferentiated cells, wherein the cells are selected from MSC, mesenchymal progenitor cells, and mesenchymal stromal cells.
The specification teaches that the undifferentiated stem cells are cells present in and isolated from adipose tissue, bone marrow, synovial membrane, cord blood, Wharton’s jelly or amniotic fluid (paragraph [0014] of pre-grant publication). As such, the specification provides evidence that the claimed undifferentiated cell exist in nature in adipose tissue, bone marrow, synovial membrane, cord blood, Wharton’s jelly or amniotic fluid. Therefore, the claims are directed to a product of nature, which is a judicial exception.
Regarding the second prong (2), claims 70-77 solely recite additional structural elements of the undifferentiated cell product. As such, the claims do not recite any additional elements or a combination thereof that integrates the judicial exception identify in prong 1 as being integrated into a practical application . Further since the claims are not meaningfully limited to any particular practical application, the generic nature of the claim appears to monopolize the claimed cell population. Thus, claim 70-77 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 70 additionally recites that the cells are “at least 60% of the cells of the population express integrin α10 subunit and are MHCII negative and CD45 negative”. Neither the claim nor the specification recite/teach that these markers are exogenously introduced but rather teach that these markers are endogenous markers of a subpopulation. The claim also recites that it is “enriched”. “Enriched” means that the cells are treated to remove other cell types. It does not change the structure of the undifferentiated cells from those found in nature. As such, no additional elements are recited that would markedly distinguish the undifferentiation cell population from the one found in nature.
The amendment to claim 70 recites that claims cell population is in a composition comprising isolated, cultured, and enriched cells. Again as discussed above and below, Myriad is clear that an isolated but otherwise unchanged natural product does not amount to significantly more than the natural product judicial exception. Also as discussed “enriched” does not structurally or functionally change the cell. Cultured indicates that the cell is in a culture, which again is the same as isolated but unchanged in structure and function of the cell. As such, the amended to the claims do not recite new additional limitations that markedly distinguish the claimed composition from it natural counterpart.
Claims 71 specifies that the cells are autologous or allogenic. This specifies the source of the cells and does not impart any further structure or function that would markedly distinguish the cell population from its natural counterpart.
Claim 72 further specifies that percentage of cells present in the population that are the undifferentiated cell population. The claim does not distinguish the cells from that cell found in nature in any way, just how many of them are present. As such, the claim does not impart a marked distinction from the product of nature.
Claim 73 specifies that the cells are in vitro. While this does impart the distinction of being isolated and place in a container of some sort outside of the body, it does not impart any distinction to the cell other than isolated.
Under the holding of Myriad, an isolated but otherwise unchanged nucleic acid was not patent eligible subject matter because it was not different enough from what exists in nature to avoid improperly tying up the future use and study of naturally occurring nucleic acid. The instant claims are analogous to this situation in Myriad. "In vitro" without any specifying description of the in vitro conditions can be interpreted as cell isolation. As such, the claimed cell product can be interpreted as isolated but otherwise an unchanged undifferentiated cell and thus not patent eligible subject matter because it is not different enough from what exists in nature to avoid improperly tying up the future use and study of the naturally occurring undifferentiated cell. As such, recitation of “in vitro" fails to amount to a marked distinction from it natural counterpart.
Regarding claims 74-75, these claims specify the antibody by which the undifferentiated cells are isolated. They do not impart any structural or functional distinction to the undifferentiated cells that would distinguish them from the natural counterpart.
Regarding claim 76, this claim describes the origin of the cell and does not impart any structural or function distinction to the undifferentiated cells that would distinguish them from the natural counterpart.
Regarding claim 77, this claim specifies additional markers expressed by the cells. The specification teaches that these are endogenous markers, not ones introduced exogenously. As such, expression of the claimed markers are a natural function the undifferentiated cell and thus do not impart any distinction to the natural product.
Overall, claims 70-77 do not meet the requirements of step 2B of the 2019PEG because the claims solely recite the undifferentiated cell that is not markedly different from its natural counterpart.
Regarding the amendments to the claim:
Claim 70, as amended and new claim 86 add product by process language to provide the method by which the claim cell population is made. Regarding Step 1A, claim 70, dependents, and new claim 86 are still a composition of matter and thus the requirements for step 1A have been meet. Regarding step 2A, prong 1, claim 70, dependents, and new claim 86 recites a cell population, thus is directed to a product of nature. As such the claims are still directed to a judicial exception as required for step 2A, prong 1. Regarding prong 2, claim 70, depends, and new claim 86 recite additional recite processes by which the claimed judicial exception is made, but does not recite any additional elements that would be deemed a practical applications. As such, under prong 2 analysis, the claims are directed to a judicial exception with no integration into a practical application. Regarding step 2B, the product by process language provide a means of making the cell population but does not evidently structurally distinguish the cells population as one markedly different from the natural counterpart discussed above. As such, the claims do not meet the requirements for step 2B.
In conclusion, claims 70-86 do not meet all the requirements of the 2019PEG and therefore deemed patent ineligible.
Response to Arguments
Applicant's arguments filed 5/18/2026 have been fully considered but they are not persuasive.
Applicant submits the claims require the cells be undifferentiated and positive for the integrin α10 subunit, which is not expressed on undifferentiated MSCs, mesenchymal progenitor cells, and mesenchymal stromal cells found in nature. In the body, α10 subunit is primary expressed on differentiated chondrocytes and is part of the mature phenotype of chondrocytes. In contrast, α10 subunit is not detectably expressed on the surface of MSCs that exist in the body. Applicant also refers to Varas 2007 which teaches that α10 subunit is not detectable in BM aspirates using FACs analysis but gain express of the α10 subunit. It is only when cells are differentiated or cultured that such cells begin to express α10 subunit. Applicant also further refers to Varas 2007 as confirming that undifferentiated cells do not express α10 subunit until they are cultivated. Applicant concludes from this fact pattern that the claimed expression of α10 subunit is a markedly different characteristic of undifferentiated cells of their claimed cell population from its natural counterpart.
In response, Applicant has not provided sufficient evidence that expression α10 subunit by a cultured MSC of their claims are a markedly different MSC, structurally and/or functionally, than the natural counterpart MSC in the human body. The art establishes marker expression alone is not an indicator of a different cell. The state of the art teaches that there are no MSC expression markers that are unique to MSCs. Varga expressly states, “There is a need for new specific MSC markers because the known markers also are expressed on other cell populations in BM”. (See p. 966, col 1, middle para starting ‘MSCs are potentially useful’). Varga further states, “To date, MSCs have been characterized by several different cell markers that are not solely expressed on MSCs and not sensitive to the state of differentiation. The co-expression of CD105 and CD166 is commonly used to define populations of mesenchymal progenitor cells… It is known that BM-derived cultured MSC as well as mesenchymal progenitor cells derived from other locations, e.g., articular cartilage… and synovium…are CD105– and CD166+. However, CD105 and CD166 are not exclusively expressed by progenitor cells. For example, cultured articular chondrocytes as well as synovial fibroblasts are closed to 100% CD105+ and CD166+…This would indicate that CD105 and CD166 are expressed on differentiated as well as potential progenitor cells in these cell populations.”
Thus while expression markers are useful in obtaining particular MSC cell populations after isolation, they are not necessarily indicators of distinctions between cell types. More particularly, the example above from the prior art teaches that MSC expression marker that are used in the art allow for obtaining and even purifying the cell population but does not exclusively indicate a specific and different cell type. These finding by Varas are consistent with teachings in the art, as evidence by Cao et al. (Stem Cell Reviews and Reports (2024) 20:1656–1666). Cao et al reports, “Culturing cells changes their properties and their gene expression. This is partly driven by selection of cells that expand better in culture, but culture-induced changes in marker expression are also common. Culture conditions, including the culture medium employed and the degree of confluence are established to affect cell growth and expression of various markers... There is a longstanding recognition that some markers, particularly CD34, can be lost during the transition to in vitro culture. Likewise, chondrocytes are widely recognized to undergo dedifferentiation to fibroblasts in culture...”. See p. 1657, col 1. Cao et al. also reports, “Cell surface marker expression is one of the criteria for defining human mesenchymal stem or stromal cells (MSC) in vitro. However, it is unclear if expression of markers including CD73 and CD90 reflects the in vivo origin of cultured cells… Osteogenic differentiation led to loss of CD106 and CD146 expression, however CD73 and CD90 were retained in > 90% of cells. We sorted freshly isolated periosteal populations capable of CFU-F formation on the basis of CD90 expression in combination with CD34, CD73 and CD26. All primary cultures universally expressed CD73 and CD90 and lacked CD34, irrespective of the expression of these markers ex vivo indicating phenotypic convergence in vitro. We conclude that markers including CD73 and CD90 are acquired in vitro in most ‘mesenchymal’ cells capable of expansion. Overall, we demonstrate that in vitro expression of many cell surface markers in plastic-adherent cultures is unrelated to their expression prior to culture.” See page 1657, abstract. Similar to the findings in Cao et al, the instant application, the Declaration dated 5/18/2026, and Varas all report the gain of cell surface expression of the α10 subunit in MSC culture that were not present in aspirates comprising MSC. The specification of the instant application and Vara teach that the MSC in culture retain proliferation capacity similar to in vivo MSC and retain the ability to differentiate into chondrocytes and other differentiated mesenchymal lineage cells similar to in vivo MSC. The prior art teaches that the gain or loss of surface expression markers of primary MSC that are placed into culture is common place and related to changes in environment and unrelated expression MSC state prior to in vitro culture. Neither the specification nor the art of Varas provide evidence that the gain of α10 subunit in MSC culture is indicative of any kind significant structural or functional distinction in the cultured MSC from its in vivo counterpart. Further it is noted that the MSC prior to culture and in culture, structurally have the same genome comprising a gene encoding α10 subunit. As such, the MSC has the capacity to express α10 subunit before and after culture, regardless of whether there are factors turning on the expression or not. Neither the specification nor the art provides evidence that the turning on of the gene for α10 subunit by the natural MSC significantly changes any particular structure or function (i.e. capable of differentiating into at least one terminally differentiated lineage cell; capacity of self-renewal) other than turning on a gene and synthesizing a protein that was not express, something the art describes as common place in the culture of MSC. However, Vara does teach putting art established external factor (i.e. FGF-2) on with MSCs isolated from aspirates turns on α10 subunit expression, indicating that the change in environment has caused the product of nature to respond in a way that is inherent to the cell (because it comprises the gene) in response to a different environmental stimuli. As such the preponderance of the evidence from the specification, declaration, and the art weigh in favor of the MSC product of nature functioning inherently in a way that it would normally function when placed in a different environment. Such an inherent function is therefore not demonstrating a different cell, but the same product of nature cell acting differently, which would not be a marked distinction of a MSC cell and population thereof from its natural counterpart. As such, the evidence does not sufficiently indicate that the differential expression of α10 subunit in MSC culture compared to in vivo MSC is a significant difference between them.
Applicant revisits Example 9 and restates that the instantly claimed MSC population is analogous to the example of the cell population that gained increase growth rate because phenotypically the MSC of the claims gain the function of expressing α10 subunit. Applicant further submits that the declaration, in addition to the specification established altered phenotype of α10 subunit in undifferentiated cells relative to those found in nature do not express α10 subunit.
In response, Examiner continues to content that Example 9 and the instant claims are not analogous because the cell in the example has a demonstrated improved characteristic over the ones found in nature. In contrast, neither the specification, declaration, nor the art provides any time of indication that the expression of α10 subunit has any particular relevance impact on the MSC cell or population thereof. However, the prior art does indicate that the MSC population is doing something it would inherently do once when placed in a different environment. While the expression of the α10 subunit is a functional change of the culture as a whole, it is not an indication of a marked distinction of the MSC over the natural product because the MSC is doing a function innate to the structure of the cell that it has when it is in its in vivo natural environment or in its supraphysiological environment of culture.
Declaration
The declaration under 37 CFR 1.132 filed 5/18/2026 is insufficient to overcome the rejection of claims 70-77 based upon 35 USC 101 as set forth in the last Office action because: The declaration does not provide evidence that MSC population is markedly different from the natural product MSC population. In contrast, the declaration and Varas provide evidence that the MSC cells are turning on their endogenous α10 subunit in response to the culture environment, meaning the culture environment is the factor that is markedly different, not the MSC cell population proper.
The declaration provides experimental evidence that MSC populations isolated and placed in their culture conditions with FGF-2 and platelet lysate cause the MSC to start expressing α10 subunit. Prior to such culture the isolated MSC do not express α10 subunit. The declaration provides evidence that this occurs with multiple MSC populations isolated from different tissues sources. The declaration teaches that this is consistent with the findings of Varas et al. The declaration reports that the different found in Vara is that the cells in their culture has 15% α10 subunit expression after culture for 21 days. The culture conditions in which the instantly claimed MSC population is derived results in 60% α10 subunit expression. As such, the evidence provided by the declaration implies that the marked distinction is the culture overall, i.e. the culture conditions with the isolated MSC population, and the method of culturing. However, it does not provide evidence that the MSC population itself is markedly different. As such, the declaration does not provide sufficient evidence of a marked distinction between the MSC cell population of the claims and its natural counterpart.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
Prosecution Insights