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 .
Status of the Claims
Claims 1-4, 6-8, and 10-19 are currently pending.
Claims 1, 8, and 18 are amended.
Claims 8 and 10-19 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 5, 9, and 20 are cancelled.
Claims 1-4 and 6-7 have been considered on the merits.
Withdrawn Rejections
The 112(a) rejections made onto claims 1-4 and 6-7 are withdrawn in light of the amendments submitted on 12/08/2025.
Maintained Rejections Necessitated by Amendment
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 1-4 and 6-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claims are directed to both a composition and a process/method of making said composition, without an apparent structural difference on the resultant product.
Claims 1-4 and 6-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. Based upon an analysis with respect to the claim as a whole, the claims do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
The claims are directed to:
A cell population with specific CD206, CD34, CD3 and CCR2 expression requirements (composition) and a method of producing a cell population by culturing mononuclear cells derived from bone marrow, umbilical cord, or peripheral blood in a medium containing serum and four or less factors selected from the list provided in claim 1 (process).
As depicted in the subject matter eligibility test below, Step 1 asks whether or not the claim is to one of the four statutory categories, and in this case the answer is: No, because the claims recite both a process and composition. Additionally, the method steps do not appear to confer a structural difference on the resultant cell population. The MPEP states in 2106.03(II) that “[i]f a claim is clearly not within one of the four categories (Step 1: NO), then a rejection under 35 U.S.C. 101 must be made indicating that the claim is directed to non-statutory subject matter”. The MPEP states that if it appears from applicant’s disclosure that the claim could be amended to fall within a statutory category then the 101 subject matter eligibility analysis should proceed. An analysis of Step 2 is provided below.
Step 2A below asks whether or not the claim is directed to a law of nature, a natural phenomenon, or an abstract idea, and in this case the answer is: yes. The claims are directed to a cell population which is a product of nature.
The claims are directed to a composition using only a nature-based product, in this case the claimed cell population, this nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. In this regard, the disclosed cell population exists entirely in nature (e.g., same genotype and phenotype potential and structure).
Claim 1 defines the cell population as having a combined 60% of cells exhibiting positive expression of CD206, CD34, and/or CD3 as well as the population containing at least 95% of cells negative for the expression of CCR2.
Liu et al (Mucosal Immunology, 2017) teaches a cell population which is comprised of macrophages which are isolated from rats (cells of natural origin) and are characterized for their expression profiles (pg. 1157, col 1, paras 3-5). Liu teaches that they have “confirmed that CCR2- macrophages express CD206” when describing Fig. 3a (pg. 1152, col 2, para 2).
Additionally, claims 6 and 7 further limist that the CD206+ cells in the population are also CXCR4+.
Beider (applied in the art rejections below) teaches the characterization of bone marrow (BM) samples from patients with multiple myeloma (MM) as well as normal patients. The BM contained M2 macrophages which are characterized by expression of CD206, and of the CD206 population there was expression of CXCR4 (Fig. 7).
Therefore, between Liu teaching that macrophages which are CCR2-, have a CD206+ phenotype and Beider teaching that macrophages which are CD206+ contain a subset of CXCR4+ macrophages, the cell population is described in the art as a product of nature.
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The claims thus encompass a cell population that is identical (no difference in characteristics) to naturally occurring cell population. Since there is no difference between the cell population claimed and naturally occurring cell population, the cell population does not have markedly different characteristics, and thus is a “product of nature” exception. In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1338-39 (Fed. Cir. 2014). Accordingly, the claimed invention is directed to an exception. Because the claimed invention does not include any additional features that could add significantly more to the exception, the claimed culture does not qualify as eligible subject matter, and should be rejected under 35 U.S.C. § 101.
Claim Interpretation
Claim 1 contains the phrase “obtained by culturing mononuclear cells derived from bone marrow, umbilical cord blood, or peripheral blood in a medium containing serum and four or less of factors selected from the group consisting of stem cell factor, interleukin- 6, FMS-like tyrosine kinase 3 ligand, thrombopoietin, and vascular endothelial growth factor”. This is a product by process limitation in which the process of culturing the cells carries little patentable weight. It is only the cell population which is taught by the prior art below, and not the process by which it was made. Product by process claims are not limited to the manipulations of the recites steps, only the structure implied by the steps, i.e. determination of patentability is based on the product itself not the method by which it was made (MPEP 2113).
Claim 2 contains the phrase “wherein the medium contains at least three factors selected from stem cell factor, interleukin-6, FMS-like tyrosine kinase 3 ligand, thrombopoietin, and vascular endothelial growth factor”. This is a product by process limitation in which the process of culturing the cells carries little patentable weight. It is only the cell population which is taught by the prior art below, and not the process by which it was made. Product by process claims are not limited to the manipulations of the recites steps, only the structure implied by the steps, i.e. determination of patentability is based on the product itself not the method by which it was made (MPEP 2113).
Claim 3 contains the phrase “wherein the serum is bovine or human serum”. This is a product by process limitation in which the process of culturing the cells carries little patentable weight. It is only the cell population which is taught by the prior art below, and not the process by which it was made. Product by process claims are not limited to the manipulations of the recites steps, only the structure implied by the steps, i.e. determination of patentability is based on the product itself not the method by which it was made (MPEP 2113).
Claim 4 contains the phrase “wherein the serum is contained in the medium at a concentration from 0.5 vol% to 10 vol%”. This is a product by process limitation in which the process of culturing the cells carries little patentable weight. It is only the cell population which is taught by the prior art below, and not the process by which it was made. Product by process claims are not limited to the manipulations of the recites steps, only the structure implied by the steps, i.e. determination of patentability is based on the product itself not the method by which it was made (MPEP 2113).
Claim Rejections - 35 USC § 102/103
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1-4 and 6-7 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 103 as being unpatentable over Beider et al (Oncotarget, “Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype”, 2014).
Regarding claim 1, Beider teaches a cell population which is derived from peripheral blood mononuclear cells (PBMCs) (Fig. 1c, and description). Beider teaches a cell population, initially characterized by CD14+ expression, which does not show any expression of CCR2, which meets the limitations of “CCR2(-) cells represent 95% or more of the cell population” (see Figure 1C). Beider teaches that this CD14+ population from peripheral blood is incubated with various types of multiple myeloma (MM) cells which can promote macrophage polarization to promote the M2 phenotype (Fig. 5 description). Beider teaches that CD206+ expression is elevated when the M2 phenotype is promoted (Fig. 5B).
Regarding claims 6 and 7, Beider teaches that 95% of the CD14+ cell population show CXCR4 expression as required by claims 6-7 (Fig. 1C).
Claims 1-4 are product by process claims in which the process of obtaining the cell population carries little patentable weight. It is only the product, which is anticipated by the prior art and not the process by which the product was made. This is because the final product (a population of mononuclear cells) is not distinguished by any particular features or characteristics resulting from the process by which it was made. As such, the limitations of the claimed process of obtaining a cell population of mononuclear cells are met by any process of obtaining a population of mononuclear cells in the prior art. Patentability of product-by-process claims is determined by the novelty and nonobviousness of the claimed product itself without consideration of the process for making it which are encompassed by the claimed process of obtaining a population of mononuclear cells of claims 1-4. Thus, the teachings of Beider anticipate the limitations of claims 1-4.
Beider is silent as to the exact percentage of the cell population which express CD206+, as required by the limitation, “wherein the total of CD206(+), CD34(+), or CD3(+) cells collectively represents 60% or more of the cell population” of claim 1. However, Beider does teach Fig. 5B (reproduced below) which shows flow cytometry data of CD206 expression before and after treatment with MM cells. It is obvious from the genuine shift of the “-MM” curve to the “+MM” curve that there is a significant increase in CD206 expression which appears to at
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least effect more than half of the MM treatment cells (especially in the +ARH77 group). Additionally, the cells are not tested for CD34 or CD3. However, The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants' generated cells differ, and if so to what extent, from the cells of the prior art. The prior art cells are the same or similar because one of ordinary skill in the art would reasonably interpret Fig. 5B of Beider as demonstrative of CD206+ expression in a majority (such as above 60%) of the cells. The cited art taken as a whole demonstrates a reasonable probability that the population of mononuclear cells of Beider are either identical or sufficiently similar to the claimed cells that whatever differences exist are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants. Clear evidence that the resulting cells of the cited prior art does not possess a critical characteristic that is possessed by the claimed method would advance prosecution.
Therefore, Beider renders the claims unpatentable.
Response to Arguments
Applicant's arguments filed 12/08/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 7) that neither Liu nor Beider teach a population of cells of the present invention “wherein the total CD206(+), CD34(+), or CD3(+) cells collectively represents 60% or more of the cell population, and CCR2(-) cell represent 95% or more of the cell population.
In response, this argument is not found persuasive. Liu is relied upon to demonstrate the population as claimed in claim 1. Liu et al (Mucosal Immunology, 2017) teaches a cell population which is comprised of macrophages which are isolated from rats (cells of natural origin) and are characterized for their expression profiles (pg. 1157, col 1, paras 3-5). Liu teaches that they have “confirmed that CCR2- macrophages express CD206” when describing Fig. 3a (pg. 1152, col 2, para 2). Thus, Figure 3a (see third plot) demonstrates a population of naturally derived cells which are 100% CCR2- and all of the cells of this population express CD206+. Additionally, the “cell population” is not limited by the size of the population and since the population of Liu demonstrates a 100% CCR2- and 100% CD206+ expressing cell population, any amount of the cells taught by Liu would demonstrate that the cell population is a product of nature. Therefore, Liu provides evidence that the cell population of claim 1 is a product of nature.
Beider is relied upon to demonstrate the population as claimed in claims 6 and 7. Beider (applied in the art rejections below) teaches the characterization of bone marrow (BM) samples from patients with multiple myeloma (MM) as well as normal patients. The BM contained M2 macrophages which are characterized by expression of CD206, and of the CD206 population there was expression of CXCR4 (Fig. 7). Therefore, between Liu teaching that macrophages which are CCR2-, have a CD206+ phenotype and Beider teaching that macrophages which are CD206+ contain a subset of CXCR4+ macrophages, the cell population is described in the art as a product of nature. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11) that the CD206 positive cells disclosed in Beider are distinct from the claimed invention because the method of Beider employs adherent monocytes after non-adherent cells are explicitly removed and the instant invention employs non-adherent cells.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the cell population being a cell population comprised of all mononuclear cells including non-adherent mononuclear cells) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The current claim 1 recites “a cell population obtained by culturing mononuclear cells” and therefore Beider meets the claimed mononuclear cells. Applicant may amend the claim to include a wherein clause defining the mononuclear cells of this invention to be inclusive of both adherent and non-adherent mononuclear cells if desired. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11) that the CD206 positive cells disclosed in Beider are distinct from the claimed invention because the method of Beider includes that adherent culture with tumor cells is essential for obtaining the polarized macrophage and this is not a necessary requirement for the cell population of the present specification.
In response to applicant's argument, the argument is not found persuasive because the invention is directed to a cell population and therefore the method of making the population of the prior art may differ from the method of making the population in the specification. The process of culturing the cells carries little patentable weight. It is only the cell population which is taught by the prior art, and not the process by which it was made. Product by process claims are not limited to the manipulations of the recites steps, only the structure implied by the steps, i.e. determination of patentability is based on the product itself not the method by which it was made (MPEP 2113). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11) that the flow cytometry data of Fig. 5B is shown in MFI and does not represent the ratio of CD206 within the cell population and thus it is technically incorrect to interpret the flow cytometry data of Fig. 5B as containing a majority expression of CD206.
In response, this argument is not found persuasive. The rejection does not assert that the MFI shift seen in the flow cytometry data of Fig. 5B positively recites that the population is more than 60% CD206+. Rather, the data was interpreted to provide a reasonable probability to one of ordinary skill in the art that the cells of Beider express a sufficiently similar level of CD206+ expression. The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants' generated cells differ, and if so to what extent, from the cells of the prior art. The prior art cells are the same or similar because one of ordinary skill in the art would reasonably interpret Fig. 5B of Beider as demonstrative of CD206+ expression in a majority (such as above 60%) of the cells. The cited art taken as a whole demonstrates a reasonable probability that the population of mononuclear cells of Beider are either identical or sufficiently similar to the claimed cells that whatever differences exist are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants.
Applicant argues (Remarks, pg. 11) that CD3(+) and CD34(+) expression is not confirmed by Beider.
In response to Applicant’s argument, the argument is not found persuasive. The claims require a “total of CD206(+), CD34(+), or CD3(+) cells collectively”. Therefore, the limitations of CD34(+) and CD3(+) expression are not currently required. Applicant may amend to include specific requirements for each of these CD markers individually. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11) that Beider does not provide the CCR2 expression in the cell population of Fig. 5B.
In response, the argument is not found persuasive. Beider states in the description of Fig. 5B that the cells tested are the “CD14-expressing macrophage population”. Beider characterizes the “CD14-expressing macrophage population” in Fig. 1C which demonstrates that the CD14-expressing macrophage population are CCR2(-). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 13-14) that the cell population produces unexpected results not predictable from the teachings of the prior art. Applicant provides examples of the importance of a population which is CCR2(-) in the application of the claimed cell population for treating ischemic diseases, inflammatory disease, or refractory wounds. Applicant concludes that the claimed cell population produces an unexpected result in its ability to treat ischemic diseases, inflammatory disease, or refractory wounds.
In response to applicant's argument that the claimed cell population produces an unexpected result in its ability to treat ischemic diseases, inflammatory disease, or refractory wounds, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Additionally, the cell population of Beider is 100% CCR2(-) and therefore would also inherently have the same capabilities. Therefore, the argument is not found persuasive.
Response to Declaration of Dr. Rica Tanaka under 37 C.F.R. 1.132
Dr. Rica Tanaka’s Declaration filled 12/08/2025 has been fully considered below.
Dr. Tanaka states at point 5 that the claimed cell population exhibits markedly different characteristics from any naturally occurring counterpart due to the claim limitations of “the total of CD206(+), CD34(+), or CD(+) cells collectively represent 60% or more of the cell population” and “ CCR2(-) cells represent 95% or more of the cell population”. Dr. Tanaka states that “these compositional features impart new properties, including enhances therapeutic effects for ischemic disease and wound healing, which were not predictable from the prior art. The observed improvements are directly attributable to the claimed features, establishing a nexus between the merits of the invention and the above evidence” (point 5). Additionally, Dr. Tanaka is thanked for providing evidence of the healing properties of the cell population in Appendix A-C.
In response to the information provided by Dr. Tanaka, the claimed invention is directed toward a product of a cell population and unfortunately not directed towards a method of use of the cell population. In response to Dr. Tanaka’s statements that the claimed cell population produces an unexpected result in its ability to treat ischemic diseases, inflammatory disease, or refractory wounds, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The cell population of Beider renders the instant cell population obvious as currently claimed, thus the prior art structure is capable of performing the intended use and meets the claim. Therefore, the evidence is not persuasive.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632