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, 7, 9-13, 18, 20, 22, 25-26, 30, 34-36, 40, 70, and 95-96 are currently pending.
Claims 1, 20, and 25 are amended.
Claims 30 and 70 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.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 2-6, 8, 14-17, 19, 21, 23-24, 27-29, 31-33, 37-39, 41-69, and 71-94 remain cancelled.
Claims 1, 7, 9-13, 18, 20, 22, 25-26, 34-36, 40, and 95-96 have been considered on the merits.
Withdrawn Rejections
The objections made onto the drawings are withdrawn in light of the supplemental drawings submitted on 03/06/2026.
The rejection made under 35 U.S.C. 112(a) are withdrawn in light of the amendments submitted on 03/06/2026.
The rejection made under 35 U.S.C. 101 is withdrawn in light of the amendments made to claim 1 on 03/06/2026.
Maintained Rejections Necessitated by Amendment
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7, 9, 10-13, 18-19, 21, 25-26, 34, 37, 40 and 95-96 are rejected under 35 U.S.C. 103 as being unpatentable over Studer et al (US20210214681A1; reference of record) as evidenced by Delgado et al (Nature, 2023), in view of Davila et al (US20190249147A1) (reference of record).
With regards to claim 1, Studer teaches a cell culture comprising iPSC ([0111]) derived microglia, astrocytes, and neurons ([0022]), wherein the neurons can include cortical projection neurons, motor neurons, dopaminergic neurons, interneurons, and peripheral sensory neurons ([0158]). The media is taught to contain 100 ng/ml of IL-34 and M-CSF [0238]). Further, the media is taught to have TGFbeta ([0167]). Studer teaches the cell seeding density of the astrocytes to be 25,000 cells/cm2 ([0254]).
Struder meets the limitations of the neurons being either GABAnergic or glutamatergic cells as evidenced by Delgado et al. Struder teaches that the neurons are selected from “cortical projection neurons, motor neurons, dopaminergic neurons, interneurons, and peripheral sensory neurons ([0158])”. Delgado demonstrates that cortical projection neurons are classified in “two classes- glutamatergic excitatory neurons and GABAergic inhibitory interneurons” (abstract). Thus, the cortical projection neurons of Struder are inherently a population of GABAergic and/or Glutamatergic as required by claim 1.
With regards to claim 7, Studer teaches that the microglia are positive for CX3CR1, P2RY12, TREM1119, and IBA1 (i.e. at least 90% positive) ([0053]).
Regarding claim 9, Studer teaches that the astrocytes are positive for GFAP and CD44 ([0022]).
Regarding claim 10, Further, Studer teaches that neurons are positive for FOXG1 and TBR1 ([0037]).
Regarding claims 11-13, Studer provides examples of microglia derived from ALS donors (donor expressing disease associates SNP) and microglia which are genetically modified to express a mutation/disruption in the TREM2 receptor ([0243]).
With regards to claim 18, Studer teaches that the cell culture is a 2D culture ([0212] and Fig. 5).
Regarding claims 25-26, the cells are taught to be cultured on a surface coated with an extracellular matrix protein, specifically Matrigel™ ([0216]).
With regards to claim 34, Further, Studer teaches that the microglia, astrocytes, and neurons are isogenic ([0248]).
Regarding claim 40, Finally, Studer teaches that the cells are cultured for at least 14 days ([0022]).
Studer does not teach that the cell seeding density of the microglial cells is between 15,000-25,000 cells/cm2 and that the cell seeding density of the neuronal cells is between 125,000-160,000 cells/cm2 as required by claim 1. Studer does not explicitly state that the astrocytes express S100 beta as required by claim 9. Studer also does not teach the cell ratios seen in claims 35-36.
However, Davila teaches compositions of neurons for in vitro screening, similar to those of Studer.
Regarding the cell seeding densities of claim 1, Studer teaches that microglial cells are seeded at 50,000 cells/cm2 and that the neurons are seeded at 200,000 cells/cm2 ([0254]). Further, Studer teaches that based on these cell seeding densities the ratio between microglia: astrocytes: neurons is 2:1:8 ([0254]). Further, Davila teaches those specific ratios may be determined by the intention of the assay, e.g., to simulate Parkinson’s disease, ADHA, Alzheimer’s Disease, etc. ([0069]). Based on the ratio of 2:1:8 taught by Studer and the very close range of seeding densities to claim 1, and the various ratios taught and made obvious by Davila, one of ordinary skill in the art would arrive at the claimed cell seeding densities by applying the desired ratios taught by Davila to the initial cell seeding densities taught by Studer.
Regarding claim 9, Davila teaches that astrocytes express S100 beta ([0041]).
Regarding claims 36 and 96, Davila teaches a 1:1 ratio of microglial cells to astrocytes as required by claim 35 and 95, as well as teaches that 1:1:5 and 2:6:1 ratios of microglia: astrocytes: neurons as required by claim 36 and 96 are obvious ([0068]/[0069]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the neural composition taught by Studer with the ratio of cells types and cell seeding ratios taught by Davila to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination for the ratios of cell types and the initial cell seeding densities because Davila teaches those specific ratios may be determined by the intention of the assay, e.g., to simulate Parkinson’s disease, ADHA, Alzheimer’s Disease, etc. ([0069]) and Studer teaches a similar neurodegenerative disease, ALS. Davila teaches achieving a desired ratio of cell types and Studer teaches very close cell seeding densities to those of the instant application. Therefore, modifying the initial cell seeding densities of Studer to reflect the desired ratio of cells taught by Davila would inherently lead one of ordinary skill in the art to the initial cell seeding densities of claim 1. One of ordinary skill in the art would have a reasonable expectation of success when combining Studer with Davila because both teach compositions of many neuron types in similar culturing strategies.
Studer does not teach the culture of the cells on a surface coated with PEI as required by claim 24.
However, Davila teaches the culture of the neurons on a surface coated with PEI as required by claim 24. Further, Davila teaches the PEI coating as an alternative to Matrigel, teaching that either can be used interchangeably ([0072]/[0073]).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the neural composition taught by Studer with the coatings taught by Davila to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination for the coating because Davila teaches the PEI coating as an alternative to Matrigel, teaching that either can be used interchangeably ([0072][0073]), and Studer already teaches the use of Matrigel. One of ordinary skill in the art would have a reasonable expectation of success when combining Studer with Davila because both teach compositions of many neuron types in similar culturing strategies.
Both Struder and Davila are silent to a comparison on phagocytic ability in the co-cultures formed as required by claim 1. However, Struder teaches that microglia are phagocytic ([0003]), and Davila teaches that microglial cells are defined as cells that are capable of phagocytosis. Additionally, Struder in view of Davila teach the claimed product and the increased phagocytic property is inherent to the claimed product. Therefore, Struder in view of Davila meet the limitations of the composition having increased phagocytic ability. MPEP 2112 states “‘[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.’ Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.” (MPEP 2112 (I)).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Studer et al (US20210214681A1; reference of record) as evidenced by Delgado et al (Nature, 2023), in view of Davila et al (US20190249147A1) (reference of record), as applied to claims 1, 7, 9, 10-13, 18-19, 21, 25-26, 34, 37, 40 and 95-96 above, and in further view of Smith et al (Journal of Neuroinflammation, 2013)(references of record).
With regards to claim 20, the limitations of the independent claim 1 are taught above. Studer teaches the media is taught to contain 100 ng/ml of IL-34 and the inclusion of M-CSF as required by claim 20 ([0238]).
Studer does not teach the exact concentration of 25 ng/ml of M-CSF in the media. However, Smith teaches the culturing of microglia in the presence of 25 ng/ml of M-CSF (abstract, methods). Further, Smith teaches that the culturing of microglia in 25 ng/ml of M-CSF caused an increase in microglia proliferation thereby forming a greater number of microglia (abstract, results).
One of ordinary skill in the art at the time of the effective filling date would have found it obvious to combine the cell culture taught by Studer with the M-CSF concentration taught by Smith to arrive at the instant invention. One of ordinary skill in the art would be motivated to combine Studer with Smith because Studer teaches the use of M-CSF and Smith teaches that the culturing of microglia in 25 ng/ml of M-CSF caused an increase in microglia proliferation thereby forming a greater number of microglia (abstract, results). One of ordinary skill in the art would have a reasonable expectation of success when combining Studer with Smith because Studer teaches the necessary steps to practice the invention with M-CSF and Smith teaches adjusting the concentration successfully.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filling date, especially in the absence of evidence to the contrary.
Claims 1 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Studer et al (US20210214681A1; reference of record) as evidenced by Delgado et al (Nature, 2023), in view of Davila et al (US20190249147A1) (reference of record), as applied to claims 1, 7, 9, 10-13, 18-19, 21, 25-26, 34, 37, 40 and 95-96 above, and in further view of Yousef et al (Oncotarget, 2015) (references of record).
With regards to claim 22, the limitations of the independent claim 1 are taught above.
Studer teaches the addition of TGF-beta in the media ([0167]), but is silent as to the exact concentration of TGF-beta.
However, Yousef teaches the addition of TGF-beta causes inflammatory patterns similar to aging (abstract). More specifically, Yousef teaches that high TGF-beta (50 ng/ml) levels induced a significant increase in B2M expression, which is related to an inflammatory response seen in older neurons, i.e., aging the cells as required by claim 22 (pg. 11967, column 2, para 1). Yousef goes on to teach that “these data are the first to suggest that similar molecular mechanisms acutely yet reversibly inhibit capacity of stem cells in old muscle and in the hippocampus of the ages brain to contribute to differentiated tissue” (pg. 11967, column 2, para 2).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the cell culture product taught by Studer with the concentration of TGF-Beta taught by Yousef to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Yousef teaches that the TGF-beta at 50 ng/ml causes aging similar to differentiation of tissue in neurons (pg. 11967, column 2) and Studer is employing the TGF-Beta in the differentiation of iPSCs into neural cells. One of ordinary skill in the art would have a reasonable expectation of success when combining Studer with Yousef because Yousef supports the use of the 50 ng/ml of TGF-beta in the making of the composition of Studer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 05/19/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 8) that Struder does not teach Gabaergic or glutamatergic neurons.
In response, this argument is not found persuasive. Although Struder does not explicitly state that the neurons are gabaergic or glutamatergic, Struder meets the limitations of the neurons being either GABAnergic or glutamatergic cells as evidenced by Delgado et al. Struder teaches that the neurons are selected from “cortical projection neurons, motor neurons, dopaminergic neurons, interneurons, and peripheral sensory neurons ([0158])”. Delgado demonstrates that cortical projection neurons are classified in “two classes- glutamatergic excitatory neurons and GABAergic inhibitory interneurons” (abstract). Thus, the cortical projection neurons of Struder are inherently a population of GABAergic and/or Glutamatergic as required by claim 1.
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 9) that Struder only discloses TGFBeta in E8/E6 media to support growth and expansion of PSCs and that this is not the use in the instant application.
In response, the argument is not found persuasive. Struder teaches that the TGFBeta in the E8/E6 medium has been proven to support somatic cell reprogramming and the instantly claimed composition is drawn to a cell culture of a culture derived from PSCs “which forms a functional model of the neural network” thus this use of TGFBeta appears to be identical to the instant invention and the argument is not found persuasive.
Applicant argues (Remarks, pg. 10) that Davila does not teach tri-cultures.
In response, the argument is not found persuasive. Davila is not relied upon to teach the tri-culture aspect of the claim. The arguments are attacking each reference individually and not the combination of references as a whole. 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). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11), in reference to the rejection employing Struder, Davila, and Smith, that Smith does not cure the alleged deficiencies of Struder and Davila.
In response, the alleged deficiencies of Struder and Davila have been addressed above. Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 11), in reference to the rejection employing Struder, Davila, and Yousef, that Yousef does not cure the alleged deficiencies of Struder and Davila.
In response, the alleged deficiencies of Struder and Davila have been addressed above. Therefore, the argument is not found 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
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