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 Application/Amendment/Claims
Applicant's response filed 07/31/2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 05/07/2025 are hereby withdrawn.
The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 2-3 and 5-15 are pending.
Claims 1 and 4 are cancelled
Claims 5-14 are withdrawn from further consideration pursuant to 37 CFR l. l 42(b), as being drawn to a nonelected invention.
Claims 2 and 3 are amended in the response filed July 16,2025.
Claims 2-3 and 15 read on the elected invention and are examined herein.
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.
Claim(s) 2, 3, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gartner et al (PLoS ONE(2012)7:7;1-26; as cited in the IDS filed 06/16/2022) as evidenced by AllCells Leukopaks (see attached data sheet; https://allcells.com/research-grade-tissue-products/leukopak/) and in view of Yang et al (Biomedical Tissue Culture ed Ceccherini-Nelli (2012) Chapter 1 p1-16; InTech. Available at http://dx.doi.org/10.5772/3071) and further in view of Riedhammer et al (Methods in Mol Bio(2015) ptII chapter 1 53-61).
This is a new rejection as necessitated by the amendments to the claims filed 07/31/2025, however the rejection relies on the fact finding set forth in the action filed 05/07/2025.
Regarding Claim 2:
The term “Lympho-Myeloid Noches (LMN)” as defined by the instant specification as “as an aggregation of cells including T cells and macrophages forming colony like structures, generated from peripheral blood mononuclear cells (PBMC), can perform de novo generation of large number of T Cells and myeloid cells, remain adherent to culture vessels” (p10 ln25-30).
Claim 2 steps a and b: Gartner teach a model of in vitro development of macrophages and T-lymphocytes from blood monocytes (p10 col 2 para 1).
Gartner disclose normal donor PBMC are recovered from leukopaks using ficoll-hypaque separation (Materials and Methods, p 20 col 2 para 3). Leukopaks are derived from peripheral blood collected from donors using a protocol that includes an anticoagulant, as evidenced by AllCells Leukopaks. This reads on collecting blood from a donor.
Claim 2 steps c and d: The teachings of Gartner are discussed above. Gartner also teach seeding cells in a cell culture container in medium containing 20% fetal bovine serum (p 20 col 2 para 3).
Gartner does not explicitly teach counting the cells, however Gartner discloses seeding the cells at a specific density (p3 col2 ¶3).
Counting cells is inherent to seeding cells at a specific density. It is not possible to seed cells at a specific cell density without first counting the cells.
Gartner does not explicitly teach resuspending the final cell pellet in culture medium containing 20% fetal bovine serum, however Gartner does disclose normal donor PBMC are recovered from leukopaks using ficoll-hypaque separation (p20 col2 para 3). One of ordinary skill in the art would understand recovering normal PBMCs using ficoll-hypaque separation methods comprises resuspending the cell pellet in the culture medium. In the disclosure of Gartner this would comprise resuspending the cell pellet in culture medium containing 20% fetal bovine serum as discussed supra.
The claim recites the term “containing” which is open claim language. Thus, while the claim requires the elements recited in the claim, it does not exclude additional unrecited elements and thus the disclosure of Gartner reads on this claim limitation.
MPEP 2111.03 reads “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”.
Regarding claim 2 step e: The teachings of Gartner are discussed above. Gartner also teach cells are cultured at 37oC (p 20 para 4).
Gartner does not teach cells are cultured (incubated) in the presence of 5% CO2.
Yang disclose culture conditions and types of growth media for mammalian cells (chapter 1, title). RPMI 1640 media is formulated for cell culture at 5% CO2 (p6 para 4). Yang teach RPMI comprises 2.0 g/L sodium bicarbonate (p7 Table 2) and that media containing 1.5-2.2 g/L sodium bicarbonate is requires 5% CO2 to maintain physiological pH of 7.2-7.4 (p14 para 4).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to incorporate the 5% CO2 culture condition taught by Yang with the method of Gartner because it would have been obvious to combine prior art elements according to now methods to yield the predictable results of cell culture under physiologic pH.
Incorporating cell culture at 5% CO2 would have led to predictable results with a reasonable expectation of success because both Gartner and Yang teach mammalian cell culture in RPMI media, and Yang teach that RPMI is formulated for use in a 5% carbon dioxide atmosphere that will provide physiologic pH, which is desirable when culturing mammalian cells for efficient cell growth and healthy cultures.
Furthermore, one of ordinary skill in the art would understand that standard cell culture conditions comprise incubating cell cultures at 37oC with 5% CO2 unless protocols explicitly direct the user to use alternative conditions.
Regarding claim 2 step f: The teachings of Gartner are discussed above. Gartner also teach Figure 1a, a microscopy image of complex colony formed in monocyte derived macrophage (MDM) cultures (p2). This reads on observing the generation of adherent LMN niches.
The instant specification defines the LMS as “an aggregation of cells including T cells and macrophages forming colony like structures, generated from peripheral blood mononuclear cells (PBMC), can perform de novo generation of large number of T Cells and myeloid cells, remain adherent to culture vessels” (p10 ln 25-30).
The MDM cultures of Gartner read on the definition of LMN as defined by the instant specification. The MDM cultures are derived from PBMC cells that adhere when seeded into plastic flasks and plates. Adherent cultures are washed multiple time to remove non-adherent cells and cultured further (p20 col 2 para 4).
The adherent cells are detached by exposure to 20mM EDTA for 10-15 min and replated, cultured for 2-4 days, washed extensively to remove non-adherent ells, and treated with IL-2 (p 3 col 2 para 3).
Large macrophages harboring small cells develop in the culture, and these cells release both non-adherent cells and adherent cells (p 3 col 2 para 3). Non-adherent cells are identified as T cells (p4 col 1 para 1). When replated, some of the non-adherent cells establish new macrophage cultures (p 4 col 1 para 3).
Thus the adherent culture taught by Gartner reads on the definition of LMN in the instant specifications.
Regarding claim 2 step g, h and i: claim 2 step i recites a “wherein” clause describing the LMN culture capability to yield mixed population of T cells and macrophages in the absence of cytokines and pure population of T cells upon culturing in the presence of certain cytokines including IL-2, IL7 and IL-15
MPEP 2111.04 states “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.”
Claim 2 step i recites the active steps “maintaining”, “removing”, and “adding”.
The “wherein” clause following the active steps in step i describes qualities of the resulting cell culture but does not require active steps or define structural limitations and is therefore not considered to be limiting to the claim.
MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.”
The teachings of Gartner are discussed above. Gartner also teach washing adherent monolayers multiple times to remove adherent cells, and feeding cultures with a complete medium exchange and removal of nonadherent cells. In some cases nonadherent cells are seeded into fresh flasks or plates to establish secondary cultures (p 20 col 2 para 3).
Gartner is silent on a specific solution used to wash non-adherent cells from adherent cells.
Riedhammer teach cell culture methods to isolate mononuclear from tissues (adherent cells) using cell culture media (RPMI-1640) as a wash medium (p 82 para 2 Materials step 1).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to combine washing cells with media, as taught by Riedhammer, with the method of removing nonadherent cells from culture, as taught by Gartner because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Combining media taught by Riedhammer with washing cells taught by Gartner would have led to predictable results with a reasonable expectation of success because both Yang and Gartner are directed to culture of mammalian cells.
Regarding claim 2 step j: The teachings of Gartner are discussed above.
Gartner do not explicitly teach collecting non-adherent cells by centrifugation of medium.
Riedhammer teach using centrifugation to collect non-adherent cells such as PBMCs (p59/60 para 10).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have combined the method of cell collection taught by Riedhammer with the method of collecting cells in suspension of Gartner because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Combining centrifugation taught by Riedhammer with cell collection taught by Gartner would have led to predictable results with a reasonable expectation of success because both methods are directed to collecting cells in suspension for further culturing and the methods are both directed at harvesting viable primary PBMC derived cells.
Regarding Claim 2 step c and claim 3: The teachings of Gartner are discussed above. Gartner also teach PBMCs are seeded in RPMI 1640 culture medium in the presence of 20% fetal bovine serum (growth medium) (p 20 col 2 para 3).
Regarding claim 15: Claim 15 does not recite any active steps. Subsections a-e of claim 15 use functional language and do not comprise active steps.
MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.”
Gartner teaches the LMN as discussed supra for claims 2-3.
MPEP 2112.01 states “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established”.
Because Gartner teaches the structural limitations of the LMN, as discussed supra, the LMN taught by Gartner also performs the functions of an LMN as described in claim 15.
Response to Arguments
Regarding Claim Rejections - 35 USC § 112
Regarding claims 2 of the Action filed 05/07/2025:
The claim was rejected because the phrase “certain cytokines including” rendered the claim indefinite. Applicant has amended the claim to omit the phrase “certain” and argues the amendment renders the claim definite.
Applicant’s arguments, see p6 last paragraph/p7 first paragraph, filed 07/31/2025, with respect to the rejection of claim 2 under 35 USC § 112 have been fully considered and are persuasive. The rejection of claim 2 under 35 USC § 112 has been withdrawn.
Regarding claim 3 of the Action filed 05/07/2025:
The claim was rejected because the trade name “Opti-MEM” rendered the claim indefinite. Applicant has amended the claim to omit the trade name “Opti-MEM” and argues the amendment renders the claim definite.
Applicant’s arguments, see p7 second/third paragraph, filed 07/31/2025, with respect to the rejection of claim 3 under 35 USC § 112 have been fully considered and are persuasive. The rejection of claim 3 under 35 USC § 112 has been withdrawn.
Regarding Claim Rejections - 35 USC§ 103
Applicant’s arguments filed 07/31/2025 have been fully considered but they are moot because the rejection under 35 USC §103 in the office action filed 05/07/2025 has been withdrawn in view of the claim amendments and claim interpretations as stated supra.
This response is directed to the aspects of the Arguments that are relevant to the instant rejection under 35 USC §103.
Regarding Remarks p7-10
Applicant submits that Gartner does not demonstrate or suggest that nurse macrophages produce both T cells and fully differentiated myeloid lineage cells in parallel. (Remarks p8 ¶3).
The disclosure of Gartner reads on the LMN of the instant claims and as defined by the instant specification, as discussed supra in the rejection under 35 USC§ 103.
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., production of both T cells and fully differentiated myeloid lineage cells in parallel) 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).
Applicant submits that the nurse macrophages of Gartner are not analogous to the LMN of the claimed method (p10 ¶2).
The disclosure of Gartner reads on the LMN of the instant claims and as defined by the instant specification, as discussed supra in the rejection under 35 USC§ 103. As discussed supra, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims.
Regarding Remarks p11-14
Specific arguments against Gartner from the step by step comparison of the claimed method with Gartner (Remarks p11-14) in which the column marks Gartner as “absent” and a specific feature is described as lacking from Gartner.
Remarks that are not marked “absent” and/or do not have s specific argument against Gartner are not addressed.
1) Applicant argues that Gartner produces macrophages which differ from the LMN niche comprising T cells and macrophages forming colony like structures as required by the instant claim (Remarks p10 para2/ p11).
The instant claim recites generating Lympho-Myeloid Niches, which as defined by the instant specification is “an aggregation of cells including T cells and macrophages forming colony like structures, generated from peripheral blood mononuclear cells (PBMC), can perform de novo generation of large number of T Cells and myeloid cells, remain adherent to culture vessels” (p10 ln25-30).
Gartner discloses a complex colony in MDM culture (fig 1a). This reads on an aggregation of cells forming colony-like structures of the instant claim. The culture of Gartner is generated from PBMC (p20 col1 ¶3). The culture disclosed by Gartner can perform de novo generation of T cells and myeloid cells; Table 1 summarizes the generation of CD4+ T cells and macrophages (myeloid cells) from the primary MDM cultures.
Thus the disclosure of Gartner reads on the LMN as defined by the instant specification.
Applicant submits the cultures of Gartner differ from the niche comprising T cells and macrophages forming colony like structures of the instant invention, however the cultures of Gartner read on the LMN as defined by the instant specification and as required by the limitations recite in the instant claims.
2) Applicant argues that seeding PBMC in culture medium containing 20% fetal bovine serum only distinguishes the instant invention from the disclosure of Gartner (Remarks p11). The instant claim recites “a culture medium containing 20% fetal bovine serum”.
The claim uses the term “containing” which is open claim language. Thus, while the claim requires the elements recited in the claim, it does not exclude additional unrecited elements. The disclosure of Gartner reads on the claim limitation as written, as discussed supra in the instant rejection under 35 USC §103.
MPEP 2111.03 reads “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”.
Gartner discloses seeding PBMC in medium containing 20% fetal bovine serum after recovery from leukopaks using ficoll-hypaque separation (p20 col2 ¶3).
Thus the disclosure of Gartner reads on “medium containing 20% fetal bovine serum” as claimed.
3) Applicant argues that the claimed method differs from Gartner in view of the incubation of the cell culture at 37°C with 5% CO2 (Remarks p12).
In response to applicant’s arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The combination of Yang and Gartner render obvious the culture of mammalian cells at 37°C with 5% CO2, as discussed supra in the rejection under USC 103.
4) Applicant argues that Gartner does not generate the LMN including T cells and macrophages forming colony like structures (Remarks p12). This argument is addressed supra in response 1) and reiterated below:
Gartner discloses a complex colony in MDM culture (fig 1a). This reads on an aggregation of cells forming colony-like structures of the instant claim. The culture of Gartner is generated from PBMC (p20 col1 ¶3). The culture disclosed by Gartner can perform de novo generation of T cells and myeloid cells; Table 1 summarizes the generation of CD4+ T cells and macrophages from the primary MDM cultures.
Thus the culture of Gartner reads on the LMN as defined in the instant specification.
5) Applicant argues the claimed method differs from Gartner in that Gartner produces a culture that differs from the LMN (Remarks p 13). This argument is addressed supra in the response to argument 1).
6) Applicant argues the claimed method differ from Gartner in that the claimed method adds fresh growth medium to the LMN (p13). Presumably Applicant is referring to claim 2 step i.
Figure 1a of Gartner discloses a complex colony in MDM culture, and as discussed supra in response 1) this reads on the LMN of the instant claim. Gartner teach cultures are fed at 3-4 day intervals with a complete medium exchange and cultures are characterized at 4-6-weeks old (p20 col2 ¶3/4). A complete media change reads on “adding fresh growth medium” and the culture reads on the LMN as defined by the instant specification.
Regarding points 1-6 of Remarks p14-16:
1) Applicant Argues the objective of the claimed method differs from the objective of Gartner.
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.
Thus the objective of Gartner is not relevant to whether the cell culture of Gartner comprises the structural and functional limitations as required by the instant claims.
2) Applicant argues the cellular mechanism of the claimed method differs from that of Gartner.
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. cellular mechanism) 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).
3) Applicant argues the culture medium differs from that of Gartner. The argument against the culture medium as disclosed by Gartner is addressed supra.
In brief: the open claim language “medium containing 20% fetal bovine serum” of the instant claim limitation does not exclude additional components, thus the medium of Gartner which contains 20% fetal bovine serum reads on the limitation as claimed.
4) Applicant argues the claimed production steps differ from that of Gartner.
The method steps as disclosed by the instant claims are the active steps as recited in the claims. Gartner and the combined references read on these steps as discussed supra in the instant rejection under USC 103.
5) Applicant argues the output of the LMN differs from that of Gartner. The LMN is defined in the instant specification as “an aggregation of cells including T cells and macrophages forming colony like structures, generated from peripheral blood mononuclear cells (PBMC), can perform de novo generation of large number of T Cells and myeloid cells, remain adherent to culture vessels” (p10 ln25-30).
Thus the requirement as required by the instant claim limitation is “T cells and myeloid cells” as required by the definition of the LMN. The claims do not recite further limitations on the “output” and thus the culture of Gartner read on the “output” as required by the instant claim limitations and as defined by the definition in the instant specification.
Applicant argues Gartner do not generate conventional immune effector 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. conventional immune effector 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).
6) Applicant argues that the T-cells generated by the claimed method differ from those of Gartner. Applicant argues the claimed LMN generates different types of T cells including CD4 T cells whereas Gartner generates CD4+ T 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. different types of T 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).
Regarding the arguments against Gartner, AllCells Leukopaks, Yang, Riedhammer individually (Remarks p16-17):
Applicant argues that neither Gartner, AllCells Leukopaks, Yang, or Riedhammer individually teach or suggest the technical steps as recited in the instant claim 2 filed 07/31/2025 (p16-17).
In response to applicant’s arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding the arguments against the combined teachings of the references (Remarks p17):
Applicant argues the combined teachings of Gartner, AllCells Leukopaks, Yang, and Riedhammer would not result in the claimed method. Applicant argues that Gartner does not produce myeloid cells in parallel. Applicant argues there is not teaching or suggestion of direct formation of adherent , multicellular LMNs from PBMCs. Applicant argues there is no teaching or suggestion of generation of T lymphocytes and fully differentiated myeloid cells within the same niche.
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. produce myeloid cells in parallel, generation of T lymphocytes and fully differentiated myeloid cells within the same niche) 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 teachings of the combined references read on the claim limitations as discussed supra in the rejection under 35 USC§ 103.
Conclusion
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 ANDREA LYNNE MORRIS SPENCER whose telephone number is (571)272-3328. The examiner can normally be reached Monday-Friday 9:00-5:00.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631