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, 4-5 and 9-12 are pending.
Claims 1, 4-5, and 9 are newly amended.
Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim and made FINAL. Election was made without traverse in the reply filed on 07/31/2023.
Claims 1, 4-5, and 9 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of the claims under 35 USC 103 is maintained as discussed below.
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.
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 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Liddelow et al. (Nature, 2017, on IDS 01/15/2021, previously cited, hereafter “Liddelow I”) in view of Williams et al. (PLoS One, 2009, on IDS 01/15/2021, previously cited) and Rivieccio et al. (The Journal of Immunology, 2005, previously cited) as evidenced by Foo et al. (Neuron, 2011, previously cited).
In regards to claim 1, in regards to step (a), Liddelow I teaches a method for generating A1 astrocytes by treating purified astrocytes derived from forebrain in media comprising 30 ng/mL TNFα for 24 hours (Abstract, p481; Methods, p488). A concentration of 30 ng/mL overlaps with the range of 0.5 ng/mL to 30 ng/mL as in claim 1, and a timing of 24 hours overlaps with the range of at least 1 day (see MPEP 2144.04).
In regards to the forebrain astrocytes, Liddelow I teaches that the method for obtaining the astrocytes derives from Foo. As evidenced by Foo, astrocytes obtained by this method strongly promote synapse formation (Summary, p799). As further taught by Liddelow I, A1 astrocytes are destructive to synapses, and form specifically in response to neuroinflammation (p481). Therefore, because the forebrain astrocytes, as taught by Liddelow I are known to promote synapse formation, and since Liddelow I teaches that A1 astrocytes are destructive to synapses and form as a result of neuroinflammation, a person of ordinary skill in the art would have recognized that the forebrain astrocytes, from which the A1 astrocytes, as taught by Liddelow I are generated, are not themselves A1 astrocytes.
Additionally, since the astrocytes are obtained directly from living forebrain tissue, they are primary astrocytes as understood in the art. Finally, Liddelow I demonstrates that the primary astrocytes (before treatment with TNFα) retained their non-activated in vivo gene profile and did not exhibit an A1-astrocyte phenotype with a variety of other factors tested (see Extended Data, Fig. 2a & b).
Liddelow I teaches that the culturing is performed in serum-free conditions (Methods, Immunopanning and cell culture, p488; p482).
Liddelow I teaches that A1 astrocytes are neurotoxic and kill neurons (and thus are cytotoxic) (p481), and that that neurite outgrowth is significantly shorter in retinal ganglion cells (RGCs) exposed to A1 astrocytes compared to controls (Extended Data Figure 5k).
Liddelow I teaches that the A1 astrocytes express CXCL10 (Figure 1, p482).
While Liddelow I teaches that published microarray datasets indicates that IFNγ promotes expression of A1-specific transcripts (markers), Liddelow I does not explicitly teach that A1 astrocytes were generated with IFNγ.
Additionally, while Liddelow I teaches that A1 astrocytes are abundant in various human neuroinflammatory and neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis (Abstract, p481; A1 astrocytes in human disease), and promotes cell death in human cells (Figure 4, p485), Liddlow I teaches that the forebrain astrocytes are derived from rats or mice, not humans specifically.
However, a person of ordinary skill in the art would have been motivated to modify the method of Liddelow I and add IFNγ because Williams teaches that IFNγ and TNFα work together to promote CXCL10 expression in a pro-inflammatory context (Abstract, p1; Figure 1, p3; p8). They would have been further motivated to add IFNγ because Williams also teaches that pro-inflammatory cytokines IFNγ and TNFα are elevated in the brains of patients with HIV-associated neurocognitive disorders (HAND,) such neuroinflammatory conditions such as HIV-encephalitis (HIVE) (Introduction, p1, p8), and a person of ordinary skill in the art would have been motivated to mimic the in vivo milieu in order to more accurately study human disease.
Furthermore, because as above Liddelow I teaches that IFNγ promotes expression of A1 markers, and because Williams demonstrates that the combination of IFNγ and TNFα promotes astrocyte CXCL10 expression in a pro-inflammatory context, it could have been done with predictable results and a reasonable expectation of success.
They would have also been motivated to modify the method of Liddelow I and use human astrocytes specifically, in order to more accurately human disease, and because as taught by Williams since CXCL10 levels are linked to disease severity, understanding its regulation could aid in the development of therapeutic intervention strategies for HAND (Abstract, p1). Furthermore, because Liddelow I discusses the role of A1 astrocytes in human disease and promotes cell death in human cells (Figure 4, p485), and because Williams teaches IFNγ and TNFα promotes astrocyte CXCL10 expression in a pro-inflammatory context in human astrocytes specifically (Astrocyte cell culture and treatment, p2), it could have been done with predictable results and a reasonable expectation of success.
In regards to the concentration of IFNγ, Williams teaches that IFNγ was used at a concentration of 50 ng/mL. While, the concentration of IFNγ is greater than the range of 0.1 ng/mL to 20 ng/mL, it is still fairly close (MPEP 2144.04(I), “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985”).
Moreover, a person of ordinary skill in the art could have arrived at a concentration range of 0.5 ng/mL to 30 ng/mL by routine optimization, and the disclosure does not point to a criticality in this amount.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Furthermore, because Rivieccio teaches that primary human astrocyte cultures can be treated with 10 ng/mL IFNγ (Results, p3721), which lies in the range of 0.1 to 20 ng/mL, a person of ordinary skill in the arts could have arrived at this concentration by routine optimization with predictable results and a reasonable expectation of success.
Moreover, a person of ordinary skill in the arts would have been motivated to reduce the amount of IFNγ used as to minimize the amount of reagents needed, which would save time and expenses. Furthermore, because Rivieccio teaches that 10 ng/mL IFNγ was effective for culturing primary human astrocyte and induced CXCL10 expression (Results, p3721), it could have been done with predictable results and a reasonable expectation of success.
In regards to step (1), Liddelow I teaches that forebrain astrocytes were cultured in serum-free conditions for 6 days (Immunopanning and cell culture, p488), which overlaps with the range of at least 24 hours.
In regards to step (2), Liddelow I teaches that following this, astrocytes were treated with TNFα for 24 hours (Immunopanning and cell culture, p488), which also overlaps with the timing of at least 1 day after the step (1).
In regards to claim 9, Liddelow I, teaches that the concentration of TNFα was 30 ng/mL and that the concentration of IFNγ can be optimized to at least 10 ng/mL (see discussion above). This would result in a 3:1 TNFα:IFNγ ratio which lies in the range of 100:1 to 1:100.
Therefore, the combined teachings of Liddelow 1, Williams, and Rivieccio render the invention unpatentable as claimed.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Liddelow et al. (Nature, 2017, on IDS 01/15/2021, previously cited, hereafter “Liddelow I”) in view of Williams et al. (PLoS One, 2009, on IDS 01/15/2021, previously cited) and Rivieccio et al. (The Journal of Immunology, 2005, previously cited), as evidenced by Foo et al. (Neuron, 2011, previously cited), as applied to claim 1 above, and further in view of Embad et al. (Stem cells and Development, 2012, previously cited).
In regards to claim 4, as discussed above, Liddelow I teaches that the astrocytes were obtained from forebrains, not pluripotent stem cells (PSCs).
However, a person of ordinary skill in the arts would have been motivated to derive astrocytes from PSCs because Embad teaches that embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), both types of PSCs, have the extraordinary ability to undergo both unlimited self-renewal and to differentiate into all cell types present in the adult organism, including specifically astrocytes, which are important as a source of therapeutic use for brain tumors and other neurological diseases (Abstract; Introduction, p404).
Furthermore, because Embad teaches methods for differentiating astrocytes from PSCs (Materials and Methods, p405; Figure 1, p406), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Liddelow 1, Williams, Rivieccio, and Embad render the invention unpatentable as claimed.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Liddelow et al. (Nature, 2017, on IDS 01/15/2021, previously cited, hereafter “Liddelow I”) in view of Williams et al. (PLoS One, 2009, on IDS 01/15/2021, previously cited) and Rivieccio et al. (The Journal of Immunology, 2005, previously cited), as evidenced by Foo et al. (Neuron, 2011, previously cited), as applied to claim 1 above, and further in view of Liddelow et al. (Immunity Review, 2017, previously cited, hereafter “Liddelow II”).
In regards to claim 5, Liddelow I teaches that in previous experiments they found that neuroinflammation and ischemia induced two different types of reactive astrocytes that they termed A1 and A2 astrocytes (p481). In regards to the difference between these subsets, Liddelow I teaches that A1 astrocytes highly upregulate many classical complement cascade genes previously shown to be destructive to synapses, while A2 astrocytes upregulated many neurotrophic factors (p481). Therefore, Liddelow posits that A1 astrocytes are harmful, while A2 astrocytes are protective (p481).
This is confirmed by Liddelow II who teaches that injuries to the CNS elicit at least two types of “reactive” astrocytes, including A1 and A2 astrocytes (Abstract, p957; Transcriptome analysis of reactive astrocytes, p959).
In comparison, Liddelow II teaches that physiologically, A1 astrocytes are involved in neuroinflammatory responses, and thus might have “harmful” functions, while A2 astrocytes are induced by ischemia, promote survival and synapse repair, and thus might have “helpful” functions (Transcriptome analysis of reactive astrocytes, p959).
Continuing, Liddelow II teaches the A1 and A2 states are a continuum of phenotype in response to inflammatory (A1 type) or ischemic (A2 type) states (Fig. 1, p959).
In regards to the method of Liddelow I, in regards to the forebrain astrocytes as used by Liddelow 1, as discussed above, Liddelow I teaches that the method for obtaining the astrocytes derives from Foo, and as evidenced by Foo, astrocytes obtained by this method strongly promote synapse formation (Summary, p799).
A person of ordinary skill in the art would have recognized that since A2 astrocytes promote synapse repair (formation), the used astrocytes as taught by Liddelow I appear to have been A2 astrocytes specifically.
This is further suggested because Liddelow II teaches that A2 and A1 astrocytes exist in a continuum, and develop an A1 phenotype in response to inflammation (Fig, 1, p959) including with inflammatory cytokine TNFα (p960-961).
However, even if the used cells as taught by Liddelow I were not A2 astrocytes specifically, a person of ordinary skill in the arts would have been motivated to use A2 astrocytes to test how the balance of A1 to A2 astrocytes affects human disease states, particularly neurodegenerative diseases such as Alzheimer’s disease, multiple sclerosis, ALS, Parkinson’s disease, and Huntington’s disease (p961-962; Fig, 1, p959).
Furthermore, because Liddelow II teaches that A1 astrocytes and A2 astrocytes are a continuum, and that A1 astrocytes can be activated by exposure to cytokines such as TNFα, as discussed above, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Liddelow 1, Williams, Rivieccio, and Liddelow II renders the invention unpatentable as claimed.
Declaration under 37 CFR 1.132
Applicant declares that the figure demonstrates that when measuring the length of neurites in neurons cultured on human astrocytes while varying the concentrations of TNFα and IFNγ no neurocytotoxity was induced by treatment with TNFα or IFNγ alone (Declaration, p2).
The declaration under 37 CFR 1.132 filed 01/21/2026 is insufficient to overcome the rejection of claims 1, 4-5, and 9 as set forth in the last Office action because: they are not germane to the rejection at hand and do not establish facts which overcome the rejection.
Claim 1 is a method for producing A1 astrocytes, not a method for inducing neurotoxicity. Thus, whether TNFα and IFNγ result in neurotoxic effects on neurons is not germane to the claims as limited.
While claim 1 states that astrocytes have neurotoxicity, this is a property of the astrocytes, not a further method step of using those astrocytes.
As discussed above, as taught by Liddelow I, A1 astrocytes are neurotoxic and kill neurons (and thus are cytotoxic) (p481) and result in neurite outgrowth that is significantly shorter in retinal ganglion cells (RGCs) when exposed to these cells (Extended Data Figure 5k). Thus, the astrocytes as taught by Liddelow I have this property.
In regards to TNFα and IFNγ, as discussed above, Liddelow I teaches a method for generating A1 astrocytes by treating purified astrocytes derived from forebrain in media comprising TNFα as claimed (Abstract, p481; Methods, p488).
Thus, a person of ordinary skill in the art would have expected development of the A1 upon exposure to TNFα.
In regards to IFNγ, as above, while Liddelow I does not explicitly teach that A1 astrocytes were generated with IFNγ, Liddelow I teaches that published microarray datasets indicates that IFNγ promotes expression of A1-specific transcripts (markers).
Furthermore, as above, a person of ordinary skill in the art would have been motivated to modify the method of Liddelow I and add IFNγ because Williams teaches that IFNγ and TNFα work together to promote CXCL10 expression in a pro-inflammatory context (Abstract, p1; Figure 1, p3; p8). They would have been further motivated to add IFNγ because Williams also teaches that pro-inflammatory cytokines IFNγ and TNFα are elevated in the brains of patients with HIV-associated neurocognitive disorders (HAND,) such neuroinflammatory conditions such as HIV-encephalitis (HIVE) (Introduction, p1, p8), and a person of ordinary skill in the art would have been motivated to mimic the in vivo milieu in order to more accurately study human disease.
Additionally, because as above Liddelow I teaches that IFNγ promotes expression of A1 markers, and because Williams demonstrates that the combination of IFNγ and TNFα promotes astrocyte CXCL10 expression in a pro-inflammatory context, it could have been done with predictable results and a reasonable expectation of success.
Response to Arguments
Applicant argues that as provided in the declaration under 37 CFR 1.132, the results demonstrate that when measuring the length of neurites in neurons cultured on human astrocytes while varying the concentrations of TNFα and IFNγ no neurocytotoxity was induced by treatment with TNFα or IFNγ alone (Remarks, p6; citing figure p2 of declaration).
As a result, Applicant argues that since TNFα and IFNγ alone showed no neurotoxicity, one of ordinary skill in the art could not conceive that combining TNFα and IFNγ could produce neurotoxic human A1 astrocytes (Remarks, p6).
Applicant’s arguments filed 01/21/2026 have been fully considered but are not found persuasive.
As discussed above, claim 1 is a method for producing A1 astrocytes, not a method for inducing neurotoxicity. Thus, whether TNFα and IFNγ result in neurotoxic effects on neurons is not germane to the claims as limited.
Additionally, while claim 1 states that astrocytes have neurotoxicity, this is a property of the astrocytes, not a further method step of using those astrocytes.
As discussed above, as taught by Liddelow I, A1 astrocytes are neurotoxic and kill neurons (and thus are cytotoxic) (p481) and result in neurite outgrowth that is significantly shorter in retinal ganglion cells (RGCs) when exposed to these cells (Extended Data Figure 5k). Thus, the astrocytes as taught by Liddelow I have this property.
In regards to TNFα and IFNγ, as discussed above, Liddelow I teaches a method for generating A1 astrocytes by treating purified astrocytes derived from forebrain in media comprising TNFα as claimed (Abstract, p481; Methods, p488).
Thus, a person of ordinary skill in the art would have expected development of the A1 upon exposure to TNFα.
In regards to IFNγ, as above, while Liddelow I does not explicitly teach that A1 astrocytes were generated with IFNγ, Liddelow I teaches that published microarray datasets indicates that IFNγ promotes expression of A1-specific transcripts (markers).
Furthermore, as above, a person of ordinary skill in the art would have been motivated to modify the method of Liddelow I and add IFNγ because Williams teaches that IFNγ and TNFα work together to promote CXCL10 expression in a pro-inflammatory context (Abstract, p1; Figure 1, p3; p8). They would have been further motivated to add IFNγ because Williams also teaches that pro-inflammatory cytokines IFNγ and TNFα are elevated in the brains of patients with HIV-associated neurocognitive disorders (HAND,) such neuroinflammatory conditions such as HIV-encephalitis (HIVE) (Introduction, p1, p8), and a person of ordinary skill in the art would have been motivated to mimic the in vivo milieu in order to more accurately study human disease.
Additionally, because as above Liddelow I teaches that IFNγ promotes expression of A1 markers, and because Williams demonstrates that the combination of IFNγ and TNFα promotes astrocyte CXCL10 expression in a pro-inflammatory context, it could have been done with predictable results and a reasonable expectation of success.
Applicant argues that Test Example 1 of the present application demonstrates that adding TNFα and IFNγ in combination significantly increases C3 expression compared to treatment with TNFα or IFNy alone (citing Figures 4 to 6), and that Example 3 of the present application demonstrates that human A1 astrocytes, which were produced by the method of the claimed invention, possess neurotoxicity (citing Figure 9) (Remarks, p6).
Applicant’s arguments filed 01/21/2026 have been fully considered but are not found persuasive.
In regards to allegations of unexpected results, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Specifically, the claims do not require specific levels of C3 expression.
Furthermore, even if they did, since Liddelow I teaches that C3 is one of the most characteristic and highly unregulated genes in A1 astrocytes (A1 astrocytes in human disease, p484), high relative levels of C3 would have been the expected result.
In regards to neurotoxicity, again as a above, Liddelow I teaches that A1 astrocytes are neurotoxic and kill neurons (and thus are cytotoxic) (p481), and that that neurite outgrowth is significantly shorter in retinal ganglion cells (RGCs) exposed to A1 astrocytes compared to controls (Extended Data Figure 5k). Thus, the A1 astrocytes as taught by Liddelow I are neurotoxic.
Applicant argues that CXCL10 is not a marker specific to A1 astrocytes, but rather, is a pan-reactive marker (Remarks, p7). Applicant argues that the pan-reactivity of CXCL10 is supported by Wang et al. (Neuroscience, 2020) (Remarks, p7-8). Continuing, Applicant argue even if Williams demonstrate that TNFα and IFNγ act synergistically to promote CXCL10 under pro-inflammatory conditions, Williams does not provide a proper reason, rationale, or motivation for using IFNγ to induce A1 astrocytes (Remarks, p7).
Applicant’s arguments filed 01/21/2026 have been fully considered but are not found persuasive.
In regards to Wang, if Applicant wishes Wang considered then it needs to be submitted on an IDS.
In regards to the pan-specificity of CXCL10, CACL10 is still an A1 astrocyte marker, and as acknowledged by Applicant, Williams teaches that IFNγ and TNFα work together to promote CXCL10 expression in a pro-inflammatory context (Abstract, p1; Figure 1, p3; p8) – which is a A1 astrocyte context.
Additionally, Williams also teaches that pro-inflammatory cytokines IFNγ and TNFα are elevated in the brains of patients with HIV-associated neurocognitive disorders (HAND,) such neuroinflammatory conditions such as HIV-encephalitis (HIVE) (Introduction, p1, p8).
Therefore, a person of ordinary skill in the art would have been motivated to combine IFNγ and TNFα because promote CXCL10 expression in a pro-inflammatory (and thus, A1 astrocyte) context and because it would mimic the in vivo milieu in order to more accurately study human disease.
Furthermore, because as above Liddelow I teaches that IFNγ promotes expression of A1 markers, and because Williams demonstrates that the combination of IFNγ and TNFα promotes astrocyte CXCL10 expression in a pro-inflammatory context, it could have been done with predictable results and a reasonable expectation of success.
Conclusion
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.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631