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 1-15 were originally filed 22 February 2022.
Claim 15 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7 April 2025.
Claims 1, 3-5, 7-9, 12-14, and 17-19 are currently under consideration.
Priority
The instant application is a continuation of now U.S. Patent 11,291,840 B2 filed 9 October 2018 and claims priority to U.S. Provisional Applications 62/569,696 (referred to herein as ‘696) filed 9 October 2017 and 62/627,966 (referred to herein as ‘966) filed 8 February 2018.
Neither U.S. Provisional Application 62/569,696 nor 62/627,966 recite or contemplate the instantly claimed method of modulating neuronal network activity. The provisional applications are drawn to a specific stimulation protocol for a specific neuronal cell culture. The specific stimulation protocol comprises using two substrate embedded gold wires to apply a 27mV/mm alternating EF to apply a biphasic rectangular wave at frequencies ranging from 0.2 Hz-200 kHz (see ‘696 pg. 13, 1st para; see ‘966 pg. 7, 3-4th para, pg. 9 last para). The frequency was either increased or decreased by 10-fold and held for 6 minutes starting with either 0.2 Hz or 200 kHz (see ‘696 pg. 13, 1st para, pg. 14, 2nd para; see ‘966 pg. 7, 4th para, pg. 9 last para). The specific neuronal cell culture comprises a 3D structure comprising cortical neurons isolated from Sprague Dawley rats (see ‘696 pg. 7, last para; see ‘966 pg. 4, 1st full para).
Applicant has argued “Figure 2 as well as the discussion which provide a broader disclosure than the specific exemplified methods” as support for claiming priority to provisional applications ‘696 and ‘966 (see Response to Non-final received 12/08/2025, referred to herein as Remarks, para spanning pgs. 6-7). Applicant does not specify which provisional application figure 2 nor any particular location in either disclosure for broader support for the claimed method. Figure 2 in both provisional application are describing a specific stimulation paradigm (e.g., specific increasing and decreasing stimulation, duration of stimulation) and specific neuronal population (e.g., cortical neuronal) among other parameters. Therefore, neither provisional application 696 nor ‘966 provide support for the broader instant claims (e.g., for any period of time, increasing at any interval, comprising any neuronal cell).
Therefore, the priority date for the instant claims 1, 3-5, 7-9, 12-14, and 17-19 is that of U.S. Application 16/154,843 filed 9 October 2018 now U.S. Patent 11,291840.
Claim Interpretation
Claim 1 is drawn to a neuronal culture comprising a population of neuronal cells and a pair or array of electrodes embedded in the substrate and in contact with a subpopulation of the neuronal cells. In the case of a pair of electrodes claim 1 in interpreted as each electrode contacting a different cell given the claim recites “a sub-population of the neuronal cells” implying more than one cell is contacted. Therefore, a pair of electrodes is in contact with 2 cells.
Claim 8 is drawn to wherein the neuronal cells are cultured for about 1-3 weeks before the alternating EF is applied. As stated above the specification defines about as a numeric value of +0.5 (see specification pg. 12 para [0041]). Therefore, claim 8 is interpreted as wherein the neuronal cells are cultured for 1-1.5 weeks to 3-3.5 weeks before the alternating EF is applied.
Claim 19 is drawn to neurons that are “adjacent” to one another. Giving the broadest reasonable interpretation adjacent neurons are those physically touching (e.g., gap junctions) or next to one another with no intervening structures (e.g., non-neuronal support cells).
Withdrawn Objections
In view of Applicant’s amendments to the specification and claims the objection to the specification is hereby withdrawn.
Withdrawn Rejections
In view of Applicant amending claim 5 the 35 USC 112(b) rejection for lack of antecedent basis is hereby withdrawn.
In view of Applicant amending claim 1 to specify increasing the alternative EF provides synchronization while decreasing the alternating EF provides desynchronized activity the 35 USC 112(a) rejection (i.e., new matter) regarding this language is hereby withdrawn. It is noted claim 1 remains rejected under 35 USC 112(a) (i.e., new matter) for new issues necessitated by amendment (see below).
In view of Applicant amending the preamble and specifying the “neuronal culture comprising” (i.e., open language) the 35 USC 112(b) rejection regarding the indefiniteness of the “modulating neuronal network activities”, “neuronal culture”, and “a neuronal network of neuronal cells” is hereby withdrawn.
In view of Applicant amending claim 9 to remove the clause “functional neuronal cells” the 35 USC 112(b) rejection of claim 9 is hereby withdrawn.
In view of Applicant amending claim 1 to specify EF is an abbreviation for electrical field the 35 USC 112(b) rejection of claim 8 is hereby withdrawn.
In view of Applicant amending claims 3 and 4 to remove recitation of “neuronal network activities” the 35 USC 112(b) rejections regarding this indefiniteness are hereby withdrawn.
In view of Applicant amending claims 7, 8, and 13 to recite “the population of neuronal cells” the 35 USC 112(b) rejections (i.e., lack of antecedent basis) are hereby withdrawn.
In view of Applicant amending claim 7 to recite “interneurons” the 35 USC 112(b) rejection of claim 7 is hereby withdrawn.
In view of Applicant amending claims 1 and 12 to clarify “the neuronal network activities” the 35 USC 112(b) rejection regarding this indefiniteness in claim 12 is hereby withdrawn.
In view of Applicant amending claim 14 to remove “fetus” and adding “child, adult, or elderly subject” the 35 USC 112(b) rejection of claim 14 is hereby withdrawn.
In view of Applicant amending claim 1 to recite a specifically “biphasic pulses” and “at a frequency ranging from 0.2 Hz to 200kHz” the 35 U.S.C. 102(a)(1) rejection over Gramowski (as cited on the PTO-892 mailed 08/27/2025) is hereby withdrawn.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
In view of Applicant’s amendments the previous enablement rejection has been modified to a scope of enablement rejection.
Claims 1, 3-5, 7-9, 12-14, and 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the particular examples disclosed in the specification (i.e., cortical neurons, 10x step up starting at 0.2 Hz to 200 kHz, for 6 minutes; see examples 3 and 8), does not reasonably provide enablement for i. any neuronal cell type, ii. any step up/down change in frequency, iii. any duration, iv. any number of sequential step up/down changes, or v. any substrate. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claim 1 is drawn to a method of electrically stimulating neuronal activity comprising providing a neuronal culture comprising a substrate supporting a population of neuronal cells. The language of claim 1 encompasses a genus of neuronal cell cultures encompassing any neuronal type (e.g., spinal cord, peripheral, sensory, or combinations thereof), with any condition (e.g., healthy, degenerative disorder), at any stage (e.g., embryonic, infant, adult), any size, and with any substrate (e.g., plastic, biological matrix, 2D, 3D). Claim 1 is also drawn to applying an alternating biphasic pulses at a frequency between 0.2 Hz to 200 kHz for a period of time and either increasing the frequency to provide synchronized neuronal network activity or decreasing the frequency to provide desynchronizing neuronal network activity wherein the neuronal network activity comprises an action potential for a neuron, spiking frequency for a group of neurons, or oscillations of neurons. The language of claim 1 encompasses a large genus of neuronal cell cultures stimulated by a broad range of initial stimulating frequencies, holding for any length of time, and then increasing/decreasing by any amount wherein the change in frequency is associated with a functional change in synchrony/desynchrony of the neuronal network activity. The specification defines synchronize as a correlated appearance in time of two or more events associated with various aspects of neuronal activity while asynchronized (i.e., desynchronized) is defined as a lack thereof (see specification pg. 12 para [0037, 0038]).
Dependent claims further limit the characterization of the neuronal network activities (claims 3-5), type of neuronal cells (claims 7, 8, 13, and 14), methods for evaluating the population of neuronal cells (claim 9), , additional steps in the method (claim 12), and the initial frequency prior to increasing/decreasing the frequency (see claims 17 and 18).
Claim 19 is drawn to the method further comprises wherein electrophysiological signals demonstrate neurons exhibit similar oscillation patterns are physically adjacent and neurons exhibiting different oscillation patterns are physically separated from each other (see claim 19).
Applicant’s disclosure teaches the major challenge in functional studies of neural networks lies in the complexity and highly variable dynamics of neuronal responses. Influential factors in neuronal response include both the stimulus itself (e.g., intensity, frequency, duration, and polarity) and intrinsic properties of a neuron (e.g., cell morphology, membrane composition, and synapse maturate state) (see specification pg. 1 para [0003]). In addition, sorting activities onto source neurons and grouping them based on common behaviors are not trivial tasks (see specification pg. 44 para [0168]; see also claim 19). The specific working example is drawn to “functional networks” wherein communities are identified based on homogenous fluorescence based discharge patterns (see specification pg. 44 para [0169]). The wide range of frequencies can activate multiple sub-populations with different responsiveness and there are binary responses to the alternating EF (see specification pgs. 42-43 para [0165]). Changes in both field polarity and EF frequency were critical for network synchrony in the “functional networks”(see specification pg. 15 para [0050], pg. 36 para [0139], pg. 43 para [0166]). An ordinary artisan would recognize using electrical stimulation to produce:
either an action potential for a neuron, spiking frequency for a group of neurons, or oscillations of neurons, and
wherein increasing the frequency of the alternating EF synchronizes one of the network activity above, or alternatively, wherein decreasing the frequency of the alternating EF desynchronizes one of the network activity above
depends not only on experimental conditions (e.g., neuronal type, density, cell culture conditions, change in frequency, duration) but also on how one defines synchrony/desynchrony.
In the working example, a biphasic rectangular wave was used to induced an EF of alternating polarity resulting in an EF of 27 mV/mm in random neuronal networks of in vitro rat cortical cultures and monitored using time lapse calcium imaging (see specification pg. 15 para [0050], pg. 34 para[0134], pgs. 54-55 para [0200] figure 1A). Network level synchronous oscillations caused sub-population specific oscillatory patterns with increasing the alternating EF frequency in 10-fold increments from 0.2 Hz to 200 kHz at 6 minute increments (see specification pg. 15 para [0050], pg. 36 para [0140-0142] figure 2B, C). Applicant’s used a community detection algorithm to sort the neurons based on the statistical significance of the differences of their calcium signals (see specification pg. 36 para [0142]). Two clusters of neuronal activity were identified based on the degree of change in calcium release (see specification pg. 37 para [0145, 0146]). Super responders were identified as having more than a 5 fold increase in calcium release with peak increases of 10 fold while non-responders were identified as having less than 5 fold increases in calcium release (see specification pg. 37 para [0145, 0146]). Using manual examination of calcium signal traces, Applicant further divided the non-responders into modest responders and noisy responders. The modest responders were identified as those neurons with a less than 5 fold increase in calcium release and synchronized activity while the remaining neurons were identified as noisy responders. Both the modest and noisy responders had peak signal levels of less than 2 fold signal increases (see specification pg. 37 para [0145, 0146]). The modest and noisy responders also exhibited synchronized calcium release although with opposite phases and noisy responders had two peaks instead of one (see specification pg. 37 para [0146], figure 3H-K). In a second working example, Applicant’s used decreasing alternating EF frequency with the same 10 fold increments, range of frequencies, and time increments resulted in no real change in calcium release of the whole network; however, clear sub-population specific amplitude and phase patterns (see specification pg. 15 para [0050], pg. 38 para [0150], pg. 39 para [0152], figure 4B, D). Applicant’s suggest there are mixed responses from different sub-populations and varying functional association of these groups depending on the EF frequency change (see specification pgs. 38-39 para [0151], figure 4B). Manually aligning individual neurons onto the original image Applicant shows two functional clusters with synchronized activity with opposing amplitudes (see specification pg. 39 para [0154], figure 5G). The two clusters were further subdivided as decreasing alternating EF resulted in changes in either synchronized phases and different signal amplitudes (i.e., cluster 2a and 2b) or different synchronized phase and the same amplitude (i.e., cluster 1a and 1b) (see specification pgs. 40-41 para [0158], figure 6B, E, and F).
Therefore, Applicant’s working example is drawn to oscillations of neurons evaluated using calcium release wherein the network is defined as those neurons that exhibited calcium release across the specific experimental parameters (e.g., increase/decrease increments, time duration). The synchronized activity (i.e., calcium release) was characterized by the degree of change in calcium signaling and timing. Desynchronization was identified from a network with a relatively flat mean activity level and a large variance wherein subpopulations had opposing synchronized activity. Applicant did not demonstrate changes in any given parameter (e.g., duration, change in frequency, location of the electrode) results in the same functional outcomes (e.g., synchronization of oscillating neurons) across different populations of neuronal cell (e.g., type, density).
It is also noted step wise increase of the alternating EF frequency from 0-200k Hz over 45 minutes synchronized signaling of a random cortical neuronal network while increasing 0-200k Hz over 9 minutes desynchronized signaling of a random cortical neuronal network (see figures 2B, 4B). Thus, the particular rate and time associated with the increase can effect whether the neuronal network activity is synchronized or desynchronized.
Applicant also discloses evoking network synchrony with point stimulation (i.e., “an electrode”) is “daunting, if not impossible, for a random network” and requires preselecting a site for stimulation, matching the initiating stimulus with the selected neuron’s responsiveness, and tailoring stimulus time series for each affected neuron (or ensembles) in the network (see specification pg. 45 para [0172]). At present, Applicant discloses it is unclear whether synchronous oscillation near the electrode can propagate to other parts of the network (see specification pg. 47 para [0175]).
The state of the art teaches neuronal networks are highly unpredictable and depend heavily on the variables of the experiment.
“it is unclear whether existing neural network models have enough predictive value to be considered valid or useful for explaining brain circuits. Given the nonlinearity of the interactions among neurons present in most neural network models, numerical simulations can result in vastly different outcomes if they have too many free parameters. Alternatively, the same outcome can be generated from many different network simulations, underspecify-ing any biological predictions” (see Yuste, R. (2015) From the neuron doctrine to neural networks. Nat Rev Neurosci. 2015 Aug;16(8):487-97, in particular pg. 494, 1st col. 2nd para-2nd col) and
“it is possible that although artificial neural networks could operate well in principle and even be very useful for engi-neering applications, in order to be applied rigorously to realistic neural circuits they may need to be constrained with quantita-tive data, which are still not available” (see Yuste pg. 494, 2nd col).
In addition, results from one particular cell type are not universally applicable across all neuronal cell types in culture. For example, the oganotypic CNS cultures are thought to more closely resemble in vivo conditions compared to the 2D monocultures however these cultures still lack cytoarchitecture, physiological perfusion and cannot be scaled to larger studies of human tissue (see Nikolakopoulou et al. (2020) Recent progress in translational engineered in vitro models of the central nervous system. Brain: 143, pgs. 3181-3213, in particular pg. 3183, 1st col. last para, pg. 3183, 2nd col. 2-3rd para). The animal derived models have different degrees of circuit complexity and brain architecture and thus do not resemble human physiology (see Nikolakopoulou pg. 3183, 2nd col. 2nd para, Table 1). Even the particular 3D structure of the culture effects the activity of a neuronal network. For example, neurospheres lose their neurogenic potential with subsequent rounds of subculturing and neurospheres have low access to oxygen and nutrients leading to the inner cells dying (see Nikolakopoulou pg. 3185, 1st col. 1st full para). Organoids are spontaneously formed which makes it difficult to create reproducible systems in terms of cell types and organization (see Nikolakopoulou pg. 3185, 1st col. 1st full para). Nikolakopoulou teaches,
“Indeed, validation, i.e. ensuring that a model faithfully recapitulates in vivo physiological and pathological processes, is essential for the translatability of any model. Such validation is highly challenging in CNS models, owing to the biological complexity of the system being reproduced. Accordingly, extensive efforts are continuously underway for determining the extent to which in vitro CNS responses are representative of their in vivo counterparts” (see Nikolakopoulou pg. 3186 para spanning cols 1-2).
In 2020 (i.e., 2 years post filing) brain organoids generated for neurodegenerative diseases including Alzheimer’s disease (AD) “only very partially simulate the pathological features of AD” (see Shou et al. (2020) The application of brain organoids: from neuronal development to neurological diseases. Front. Cell Dev. Biol. 8:579659, in particular pg. 8, 2nd col. 1st para). In addition, Shou teaches,
“the dynamic cellular composition, structure, maturity, crosstalk between types of cells, etc., occur during brain development and aging. It is still a great challenge to mimic well the complexity of the human brain with organoids in a spatiotemporal pattern. Brain organoids for some brain structures such as the hippocampus and the cerebellum have not been generated yet” (see Shou pg. 8 para spanning cols 1-2).
Prajumwongs teaches there are challenges in using human embryonic stem cells (hESCs) to study neurological disorders in vitro, including efficiently deriving specific neuronal derivatives and an inability to spatial organize as precisely as cell-specific microdomains within the embryo (see Prajumwongs et al. (2016) Human Embryonic Stem Cells: A Model for the Study of Neural Development and Neurological Diseases, Stem Cells International, 2958210, 9 pages, in particular para spanning pgs. 6-7). In addition, “use of hESC-derived neural derivatives to explore brain development and disease mechanisms is still in a developing phase” (see Prajumwongs pg. 7, 1st col. 1st para).
The source of the electrical field can affect the stimulation of a neuronal network. For example Ye teaches,
“Although the electric and magnetic stimulations share the same biophysical mechanisms in activating the neurons, they are not interchangeable in neither clinical nor experimental practices. At a macroscopic tissue level, the electric field further from the stimulating electrodes may be significantly dispersed by the non-homogenous tissue conductivity during electric stimulation. In contrast, the induced electric field may be less dispersed during magnetic stimulation because the magnetic field may penetrate through the tissue without significant attenuation” (see Ye and Steiger (2015) Neuron matters: electric activation of neuronal tissue is dependent on the interaction between the neuron and the electric field. Journal of Neuro Engineering and Rehabilitation 12:65, in particular pg. 2, 2nd col. last para).
Applicant’s own publication discloses translating the findings from the working example into an effective neuromodulation application requires identification of specific parameters including the upper limit of the EF frequency and time variants of frequency change (see Tang-Schomer et al. (2018) Cortical Network Synchrony Under Applied Electrical Field in vitro. Front. Neurosci. 12:630, in particular pg. 14, 2nd col. 2nd para). In addition, the effects of alternative waveforms (e.g., sinusoidal) are unknown and the crude temporal resolution (i.e., 1 min imaging interval) reduces the precision of correlations between stimulation conditions and neuronal responses (see Tang-Schomer pg. 14, 2nd col. 3rd para). Therefore, Applicant’s own teachings suggest the instantly claimed method is not an effective method for synchronizing/desynchronizing an action potential for a neuron, spiking frequency for a group of neurons, or oscillations of neurons by increasing/decreasing the frequency of the alternating EF across the breadth of the instant claims.
Accordingly, regarding claims 1, 3-5, 7-9, 12-14, and 17-19 in the absence of substantive direction or guidance in the instant specification, the entire scope of experimentation required to use the instantly claimed method encompassing applying 0.2 Hz-200 kHz alternative EF from any source (e.g., alternating current, electromagnetic) to any population of neuronal cells comprising any species, type, number, or structure of neuronal cells in culture (e.g., hippocampal, cortical, 2D, 3D, rodent), with any substrate (e.g., 2D, 3D, biological matrix, plastic) for any period of time and then increasing/decreasing a frequency by any amount that wherein increasing the frequency provides for synchronized neuronal network activity or decreasing the frequency provides for desynchronized activity let alone for those neuronal cell cultures that model either “normal” brain functions or neurological disorders such as Alzheimer’s Disease is left to those skilled in the art. The present claims and disclosure amounting to nothing more than an invitation to the skilled artisan to develop such embodiments. Given the resource-intensive nature of the required experimentation, the skilled artisan would reasonably conclude that such experimentation would be unnecessarily, and improperly extensive and undue.
Applicant's arguments filed 8 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues the following:
adjusting the time/frequency is a matter of routine optimization” and points to example 15 generally (see Remarks pg. 8, 2nd para),
the specification provides sufficient guiding principles and constraints to implement the method without undue experimentation regardless of the specific neuronal culture being used (see Remarks pg. 8, 3rd para),
there is a clear framework, i.e., defined operational bounds, directional outcomes, measurable endpoint (see Remarks pg. 8, #1-3), and
given typical laboratory constraints the range of realistic combinations of timing and duration is finite and manageable (see Remarks pg. 8 last para).
First, Applicant provides no objective evidence or sound scientific reasoning to support such a contention; rather, it appears to be nothing more than attorney argument. As set forth in the MPEP at 2145, "The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).”
Second, even if the myriad of parameters Applicant argues could be optimized through experimentation, this experimentation would be highly unpredictable. The experimentation required amounts to trial and error until the necessary combination of parameters including:
an initial frequency within 0.2 Hz to 200 kHz,
ii. time duration at the initial frequency,
iii. degree of frequency increase/decrease,
iv. time duration at the second frequency,
v. number of repeated cycles of increasing/decreasing frequency, and
vi. with a pair of electrodes or array of electrodes in contact with a sub-population of the neuronal cells
was identified which provides synchronization/desynchronization of either i. an action potential of a neuron, ii. spiking frequency for a group of neurons, or iii. oscillations of neurons as a result of said increase/decrease of the frequency. This is further compounded by the unpredictability of the particular neuronal culture (e.g., composition, neuronal cell type, size, density, species) and substrate (e.g., 2D, 3D, biological matrix, plastic). Applicant’s single working example of both synchronization and desynchronization utilized a single specific value for each of these parameters and did not provide evidence that one or more of these parameters could be altered and have the same effect nor did Applicant demonstrate that these single specific values result in similar results across different neuronal types (e.g., peripheral nerves, spinal nerves) nor population sizes of cortical neurons.
Therefore, for the reasons stated above and the reasons made of record the 35 USC 112(a) rejection (i.e., scope of enablement) of claims 1, 3-5, 7-9, 12-14, and 17-19 is hereby maintained.
Claims 1, 3-5, 7-9, 12-14, and 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to a method of electrically stimulating neuronal activity comprising providing a neuronal culture comprising a substrate supporting a population of neuronal cells. The language of claim 1 encompasses a genus of neuronal cell cultures encompassing any neuronal type (e.g., spinal cord, peripheral, sensory, or combinations thereof), with any condition (e.g., healthy, degenerative disorder), at any stage (e.g., embryonic, infant, adult), any size, and with any substrate (e.g., plastic, biological matrix, 2D, 3D). Claim 1 is also drawn to applying an alternating biphasic pulses at a frequency between 0.2 Hz to 200 kHz for a period of time and either increasing the frequency to provide synchronized neuronal network activity or decreasing the frequency to provide desynchronizing neuronal network activity wherein the neuronal network activity comprises an action potential for a neuron, spiking frequency for a group of neurons, or oscillations of neurons. The language of claim 1 encompasses a large genus of neuronal cell cultures stimulated by a broad range of initial stimulating frequencies, holding for any length of time, and then increasing/decreasing by any amount wherein the change in frequency is associated with a functional change in synchrony/desynchrony of the neuronal network activity. The specification defines synchronize as a correlated appearance in time of two or more events associated with various aspects of neuronal activity while asynchronized (i.e., desynchronized) is defined as a lack thereof (see specification pg. 12 para [0037, 0038]).
Dependent claims further limit the characterization of the neuronal network activities (claims 3-5), type of neuronal cells (claims 7, 8, 13, and 14), methods for evaluating the population of neuronal cells (claim 9), , additional steps in the method (claim 12), and the initial frequency prior to increasing/decreasing the frequency (see claims 17 and 18).
Claim 19 is drawn to the method further comprises wherein electrophysiological signals demonstrate neurons exhibit similar oscillation patterns are physically adjacent and neurons exhibiting different oscillation patterns are physically separated from each other (see claim 19).
As stated above Applicant has provided a working example of a random 3D rat cortical neuronal network wherein 10 fold increases up to 200 kHz of alternating current with a biphasic rectangular wave with alternating polarity for 6 minutes at each frequency resulted in synchronized calcium release of neurons wherein particular subpopulation could be identified by unique synchronized phases and amplitudes (see specification pg. 34 para [0134], pg. 36 para [0140, 0141], figure 2B, 3 H, I; see above). In a second experiment the alternating frequency was decreased using the same step-wise parameters with no significant change in calcium signaling however increasing variation in calcium signaling over time (see specification pgs. 39 para [0154, 0155], figure 4B; see above).
Applicant’s disclosure teaches the challenges in studying neuronal lies in the complexity and highly variable dynamics of neuronal responses. Influential factors in neuronal response include both the stimulus itself (e.g., intensity, frequency, duration, and polarity) and intrinsic properties of a neuron (e.g., cell morphology, membrane composition, and synapse maturate state) (see specification pg. 1 para [0003]). The specific working example is drawn to “functional networks” wherein the wide range of frequencies can activate multiple sub-populations with different responsiveness (see specification pgs. 42-43 para [0165], pg. 44 para [0169]). Changes in both field polarity and EF frequency were critical for network synchrony (see specification pg. 15 para [0050], pg. 36 para [0139], pg. 43 para [0166]). Applicant’s published work discloses translating the findings from the working example in an effective neuromodulation application requires identification of specific parameters including the upper limit of the EF frequency and time variants of frequency change (see Tang-Schomer pg. 14, 2nd col. 2nd para). In addition, the effects of alternative waveforms (e.g., sinusoidal) are unknown and the crude temporal resolution (i.e., 1 min imaging interval) reduces the precision of correlations between stimulation conditions and neuronal responses (see Tang-Schomer pg. 14, 2nd col. 3rd para).
The state of the art teaches the particular neuronal cell and structure of the neuronal network will affect the activity of the neuronal network (see Nikolakopoulou pg. 3183, 1st col. last para, pg. 3183, 2nd col. 2-3rd para, Table 1; see above). For example, neurospheres have low access to oxygen and nutrients leading to the inner cells dying whereas organoids are spontaneously formed which makes it difficult to create reproducible systems in terms of cell types and organization (see Nikolakopoulou pg. 3185, 1st col. 1st full para). Nikolakopoulou teaches,
“Indeed, validation, i.e. ensuring that a model faithfully recapitulates in vivo physiological and pathological processes, is essential for the translatability of any model. Such validation is highly challenging in CNS models, owing to the biological complexity of the system being reproduced. Accordingly, extensive efforts are continuously underway for determining the extent to which in vitro CNS responses are representative of their in vivo counterparts” (see Nikolakopoulou pg. 3186 para spanning cols 1-2).
Thus, an ordinary artisan would recognize Applicant’s working example indicates the functional outcome of synchronized/desynchronized neuronal network activity (i.e., an action potential of a neuron, the spiking frequency for a group of neurons, or oscillations of neurons) is feasible but does not sufficiently support these functional outcomes using either these parameters in different neuronal populations (e.g., cell type, species, composition) in cultures with different sizes, density, and age, nor does it suggest deviating from the parameters in the working example in an identical population would have the same functional outcomes. Applicant’s specification discloses the particular working examples provide, “an easy to use testbed” for further experimentation and the invention “relates generally to models and methods to modulate neuronal network activities” (see specification pg. 48, para [0176], pg. 1 para [0001]). In addition, an ordinary artisan cannot envision the size (e.g., 5 fold increase in frequency) or duration (e.g., for 3 minutes or 30 minutes) of the change in alternating frequencies required to either synchronize or desynchronize either an action potential of a neuron, a spiking frequency for a group of neurons, or oscillations of neurons the particular protocol disclosed. The synchronization and/or desynchronization of the neuronal population depends not only on experimental conditions (e.g., neuronal type, density, cell culture conditions, change in frequency, duration) but also on how one defines synchrony/desynchrony and vicinity.
One of skill in the art would reasonably conclude that the disclosure fails to provide a method representative of the breadth of i. populations of neuronal cells (e.g., model normal brain functions, model neurological disorders, Alzheimer’s disease), ii. neuronal cell compositions (e.g., size, type, structure, or source of neuronal cells), iii. the range (e.g., 2 fold, 5 fold increase/decrease), or duration (e.g., milliseconds vs minutes) of alternating EF frequencies wherein synchrony/desynchrony is achieved, and iv. the particular substrate. Thus, the claimed subject matter is not supported by any adequate written description and therefore, Applicant was not in possession of the claimed invention.
Applicant's arguments filed 8 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues the following:
the specification provides sufficient guiding principles to bridge the gap between the feasibility example and the full scope of the claims (see Remarks pg. 10 last full para),
the method does not rely on replicating in vivo structural complexity but rather leverages the fundamental, universal electrophysiological properties that all mammalian neurons share (see Remarks para spanning pgs. 10-11, para spanning pgs. 11-12), and
the invention provides a clear, predictable mechanism and defined boundary conditions that allow for routine optimization by the ordinary artisan (see Remarks pg. 11 #1-3).
First, Applicant provides no objective evidence or sound scientific reasoning to support such a contention; rather, it appears to be nothing more than attorney argument. As set forth in the MPEP at 2145, "The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).”
Second, Applicant has not pointed to any location in the disclosure that “bridges the gap” between using a population of neuronal cells comprising a random cortical neuron culture derived from rats to different population of neuronal cells. For example, a culture of peripheral neurons, spinal cord neurons, neurons from non-mammalian sources. In fact the specification discloses, “neuronal sensitivity depends on the stimulus as well as the cell’s intrinsic properties, channel protein and receptor composition, synapse maturate state, and cell morphology” (see specification pg. 2 para [0003]). Applicant even discloses the working example is not drawn to any population of neuronal cells rather the working example “leverages the fundamental, universal electrophysiological properties that all mammalian neurons share” (see Remarks pg. 10, 1st para). Applicant’s assertion the method relies on leveraging fundamental, universal electrophysiological properties of neurons is not accurate (see Remarks para spanning pgs. 10-11, para spanning pgs. 11-12). For example, in one embodiment the claim requires the functional outcome of synchronized oscillations of neurons in a population of neuronal cells after increasing the frequency of the alternative EF. While cortical neurons exhibit the “fundamental response” of an action potential within the claimed frequency (which spans several orders of magnitude); it is not that specific response that is claimed. The claim is drawn to wherein that fundamental response (e.g., action potential) transitions from a desynchronized state (e.g., random firing) at the initial frequency to a synchronized state, i.e., more than one neuron both temporally and in magnitude, after increasing the frequency. Applicant teaches synchronized activity involves intrinsic molecular programs at the cellular level and large scale information processing at the network level (see specification pg. 1 para [0002]). Furthermore, two major challenges in functional studies are the complexity of neuronal networks and the highly variable neuronal responses (see specification pg. 2 para [0003]). Cortical neuron cultures naturally exhibit bursting activities and a propensity for synchronized bursting as cultures mature (see specification pg. 2 para [0004]). Therefore, the altered excitability (i.e., depolarization) and plasticity (i.e., how the network connections are formed/maintained) directly impact the synchrony/desynchrony of action potentials across more than one neurons in a population of neurons.
Therefore, for the reasons made of record and the reasons set forth above the 35 USC 112(a) rejection (i.e., written description of claims 1, 3-5, 7-9, 12-14, and 17-19 is hereby maintained.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-5, 7-9, 12-14, and 17-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In addition, claim 1 is drawn to either increasing or decreasing the frequency of the alternating EF to provide synchronized/desynchronizing neuronal network activity. It is unclear when a neuronal network activity is considered synchronized or desynchronized. For example, is a neuronal network synchronized when 30% of neuronal cells have a correlated appearance in time of two or more events associated with various aspects of neuronal activity (see specification pg. 12 para [0037]).
Claim 1 is drawn decreasing the frequency of the alternating EF to provided desynchronized neuronal network activity. The recitation of “desynchronized” implies the neuronal network activity is synchronized prior to the change in frequency of the alternating EF; therefore, when a neuronal network activity is considered synchronized impacts whether the change in frequency desynchronizes the neuronal network activity. Furthermore, it is unclear when a neuronal network activity is considered desynchronized. For example, is a population of neurons wherein 30% of the neurons are oscillating considered synchronized, or alternatively, is synchronized limited to all neurons in the population. Alternatively, is a neuronal network desynchronized if a subpopulation of the 30% oscillating neurons has decreased by 1% or is desynchronized limited to a 10% reduction.
Regarding claim 3, it is unclear when a neuronal culture is considered to “model” normal brain functions and when they do not. For example, are there particular characteristics (e.g., size of the population, firing patterns, number of connections) necessary to be within the scope of a “model”. To put another way, is a neuronal culture with inherently aberrant signaling treated with a small molecule to regulate signaling within the scope of an “in vitro model of a subject with normal brain functions”. Alternatively, is the mere presence of a neuronal network activity (e.g., oscillation of neurons) within the scope of modeling normal brain function or does said neuronal culture have to match additional parameters (e.g., frequency, type, and degree) exhibited in normal. It is also unclear what standard is used to define normal brain functions. For example, is normal brain function drawn to healthy controls or alternatively is normal referring to what is typical for a particular subject population (e.g., typical epileptic subject).
Claim 4 it is unclear when a neuronal culture is considered to “model” neurological disorders and when it does not. For example, are there particular characteristics (e.g., size of the population, firing patterns, number of connections) necessary to be within the scope of a “model”. To put another way, is a neuronal culture with inherently healthy signaling treated with a small molecule to alter signaling within the scope of a “model of a subject with a neurological disorder”. Alternatively, is the mere presence of a neuronal network activity (e.g., oscillation of neurons) within the scope of modeling a neurological disorder or does said neuronal culture have to match additional parameters (e.g., frequency, type, and degree) exhibited in subjects with a neurological disorder.
Claim 9 is drawn to wherein the population of neuronal cells are evaluated by specific methods (e.g., physiological measurement). The scope of the evaluation is unclear. For example, is claim 9 drawn to the methods of claim 1 further comprises evaluating the population of neuronal cells of claim 9, or alternatively, are the network activities (e.g., oscillation of neurons) of a population of neuronal cells evaluated using the methods set forth in claim 9.
Claim 12 is drawn to detecting neuronal communities of similar activity patterns. It is unclear when activity patters are considered similar and when they are not. For example, are neuronal communities that exhibit synchronized activity but in different phases considered within the scope of similar activity. Alternatively, are neuronal communities that release the same amount of calcium but are not synchronized considered within the scope of similar activity.
Claim 14 recite the limitation "the neuronal cells" in line 1. There is insufficient antecedent basis for this limitation in the claims.
Applicant's arguments filed 8 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant has asserted that synchronization is readily observable and asserts what desynchronization is “typically” (see Remarks pg. 13 two bullet points).
First, Applicant provides no objective evidence or sound scientific reasoning to support such a contention; rather, it appears to be nothing more than attorney argument. As set forth in the MPEP at 2145, "The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).” The assertion that synchronization is readily observable in real time because activities show up as “coherent lighted waves when using imaging methods such as calcium signaling” is insufficient (see Remarks pg. 13, 1st bullet). The indefiniteness is not drawn to the manner (e.g., calcium signaling) or the ease of assessing the synchronized neuronal network activity (e.g., oscillation of neurons) but the parameters relied upon for determining synchronization. For example, does a population of neuronal cells wherein 70% of the neurons in the vicinity of a pair or array of electrodes are oscillating at the same time with the same calcium signaling release exhibit synchronized neuronal network activity, or alternatively, does a population of neuronal cells wherein 30% of the neurons in the vicinity of a pair or array of electrodes are oscillating at the same time with the same calcium signaling release exhibit synchronized neuronal network activity. In both cases the “coherent lighted waves” are observed readily; however, it is unclear in which example the neuronal activity (i.e., oscillations) is or is not within the scope of synchronized. In addition, Applicant’s assertion desynchronization is definite relies on a general non-limiting statement regarding how desynchronization “typically begins with an initial suppression”.
Applicant has not addressed the indefiniteness of “model” (see claims 3 and 4), “normal brain functions” (see claim 3), the methods for evaluating the population of neuronal cells (see claim 9), “similar activity patterns” (see claim 12), and the antecedent basis of “the neuronal cells” (see claim 14). Therefore, the 35 USC 112(b) rejection over these claims is hereby withdrawn.
Applicant’s assertion the terms are clear and definite is not sufficient to overcome the 35 USC 112(b) rejection.
Claim Rejections - 35 USC § 102
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.
Claims 1, 3, 7-9, 12, and 17-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tang-Schomer published 21 September 2018.
Tang-Schomer discloses applying an alternating EF using silk protein film-embedded gold wires at frequencies ranging from 0.2 Hz-200 kHz via a biphasic rectangular wave to a random 3D cortical neuron cell culture derived from Sprague Dawley rates (see Tang-Schomer pg. 3, 1st col. 3-4th para, 2nd col. 1st full para, pg. 4, 5th para). Specifically, increasing or decreasing the frequency by 10 fold for 6 minutes per condition (see Tang-Schomer pg. 4, 2nd col. last para, para spanning pgs. 7-8). Increasing the frequency of the alternating EF resulted in synchronizing oscillations of cortical neurons observed via calcium release while decreasing lead to desynchronization of oscillations of cortical neurons (see Tang-Schomer pg. 4, 2nd col., 5-6th para, pg. 6, 2nd col. last para, pg. 8, 1st col. 1st full para, pg. 9, 1st col. 3rd para-2nd col. 1st para, figure 2B, 3B, 4B, 4D, and 5B). This is pertinent to instant claims 1, 7, and 17-19.
Regarding claim 3, the cortical neurons were isolated from a healthy embryonic day 18 Sprague Dawley rats; therefore, the neuronal culture is an in vitro model of a subject with normal brain functions (see Tang-Schomer pg. 3, 1st col. last para).
Regarding claim 8, Tang-Schomer discloses the simulated cultures were 14-16 days in vitro (see Tang-Schomer pg. 3, 2nd col. 1st para).
Regarding claims 9 and 12, calcium release (i.e., physiological measurement) was assessed during stimulation (see Tang-Schomer pg. 3, 2nd col., 3rd and 5th para). In addition, a local greedy-optimization algorithm was used to determine the best number of communities and compostion of each community for identifying sub-populations with similar activity patterns (see Tang-Schomer pg. 4, 1st col. 2nd para-2nd col. 1st para, 2D).
Applicant's arguments filed 8 December 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant has filed a Declaration under 37 CFR § 1.130(a) (referred to herein as Declaration; see Remarks pg. 14 middle of the page). When submitting a Declaration to disqualify art under 35 USC 102(b)(1) Applicant must provide the following:
an unequivocal statement from the inventor or a joint inventor that the inventor or joint inventor (or some combination of named inventors) invented the subject matter of the disclosure and
accompanied by a reasonable explanation of the presence of additional authors, may be acceptable in the absence of evidence to the contrary. See In re DeBaun, 687 F.2d 459, 463, 214 USPQ 933, 936 (CCPA 1982) (see MPEP § 2155.01).
The declaration provides a reasonable explanation for the presence of Taylor Jackvony as a graduate student working under Min-Tang Schomer’s (i.e., inventor) direction, and therefore is not an inventor of the instant disclosure. However, the declaration discloses Sabato Santaniello as a “collaborator” without specifying which portions of the Tang-Schomer disclosure (as cited on the PTO-892 mailed 08/27/2025) Sabato Santaniello collaborated on (i.e., someone who works jointly/invented) (see Declaration pg. 4 #3). Applicant’s Declaration does not provide a reasonable explanation for the presence of Sabato Santaniello on the cited Tang-Schomer disclosure.
Therefore, the 35 USC 102(a)(1) rejection over Tang-Schomer is hereby maintained.
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.
Claims 4, 5, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Tang-Schomer as evidenced by Golbe (see Golbe et al. (2014) Parkinson’s Disease Handbook. American Parkinson Disease Association, pgs. 1-44).
Tang-Schomer discloses,
“Numerous studies, both in vitro and in vivo, have focused on the mechanisms that sustain oscillations and their synchronization as well as on the relationship between neural oscillations and network dynamics, e.g., for a review, see (Buzsaki and Draguhn, 2004). Abnormal increments in synchronization are reported as a key component in chronic neurological disorders, e.g., Parkinson’s disease and epilepsy, and in the impairment of decision-making capabilities” and
“The system provides an easy-to-use testbed for reproducing pathological oscillatory activities in large neural populations as well as studying the effects of exogenous inputs (e.g., chemical compounds or novel neuromodulation approaches) on neural oscillations” (see Tang-Schomer pg. 14, 1st col. 2nd para).
Therefore, a person of ordinary skill in the art would have modified the stimulation paradigm anticipated by Tang-Schomer (see above) to model neurological disorders such as Parkinson’s Disease as the system provides an easy-to-use testbed for reproducing pathological oscillatory activities and for studying the effects of exogenous inputs. In addition, a person of ordinary skill in the art would have substituted the embryonic neuronal culture for an adult neuronal cell culture as Tang-Schomer teaches abnormal increments in synchronization are a key component in Parkinson’s Disease a disease affecting primarily adults as evidence This is pertinent to instant claims 4, 5, and 13.
Regarding claim 14, a cell culture derived from an adult or elderly subject naturally flows from substituting the normal neuronal cells taught by Tang Schomer for the Parkinson’s Disease neuronal cell culture rendered obvious by Tang Schomer given Parkinson’s Disease onset predominately occurs in adults or elderly subjects as evidenced by Golbe (see Golbe pg. 1, 3rd para).
The following rejections are necessitated by amendment.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
New Matter
Claims 1, 3-5, 7-9, 12-17, and 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification does not disclose or contemplate a method of synchronizing/desynchronizing a neuronal network activity wherein said activity is “an action potential for a neuron” (see claim 1, 2nd to last line). The specification is drawn to synchronizing/desynchronizing the same neuronal network activity across more than one neuron (see specification pg. 1 para [0001]). Therefore, reciting an action potential (i.e., singular) for a neuron (i.e., singular) is new matter that reaches beyond the specification as originally filed because the specification never contemplated the particular subgenus encompassed by the claim language.
In addition, the specification does not disclose or contemplate a method wherein “increasing the frequency of the alternating EF to provide synchronized neuronal network activity in the vicinity of the pair or array of electrodes” or likewise “decreasing the frequency of the alternating EF to provide desynchronized neuronal network activity in the vicinity of the pair or array of electrodes (see claim 1, lines 11-14). The specification is drawn to either increasing the frequency to provide synchronized neuronal activity or decreasing the frequency to provide for desynchronized neuronal network activity (see specification para [0007] spanning pgs. 3-4). Therefore, reciting the subgenus of a particular region wherein the synchronization/desynchronization of the neuronal network activity occurs is new matter that reaches beyond the specification as originally filed because the specification never contemplated the particular subgenus encompassed by the claim language.
In addition, the specification does not disclose or contemplate a method wherein “neurons with similar oscillation patterns are physically adjacent to each other” or likewise “neurons with different oscillation patterns are physically separate from each other” (see claim 19). The specification is drawn to either increasing the frequency to provide synchronized neuronal activity or decreasing the frequency to provide for desynchronized neuronal network activity (see specification para [0007] spanning pgs. 3-4). Applicant’s working example identifies this particular result in the specific neuronal cultures used; however, the disclosure does not contemplate characterizing physical proximity of individual neurons with similar/different neuronal network activity, specifically oscillation patterns. Therefore, reciting the subgenus of this particular attribute, i.e., geographical proximity of synchronized or desynchronized oscillating neurons is new matter that reaches beyond the specification as originally filed because the specification never contemplated characterizing this particular subgenus of attribute encompassed by the claim language.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-5, 7-9, 12-14, and 17-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is drawn to wherein synchronized/desynchronized neuronal network activity occurs “in the vicinity” of a pair or array of electrodes. It is unclear when a neuronal cell is considered in the vicinity and when it is not.
Claim 1 is also drawn to wherein the neuronal network activity is “an action potential for a neuron” which is singular while the claim is also drawn to synchrony/desynchrony which requires more than one neuron. Therefore, it is unclear how the neuronal network activity which necessarily requires more than one can be a singular event in a singular neuron.
Claim 3 recites the limitation "the culture" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 17 is drawn to wherein the alternating EF is initially a low frequency within the range of 0.2 Hz to 200 kHz. It is unclear when the initial frequency is considered low and when it is not.
Claim 18 is drawn to wherein the alternating EF is initially a high frequency within the range of 0.2 Hz to 200 kHz. It is unclear when the initial frequency is considered high and when it is not.
Claim 19 is drawn to “wherein analyzing the acquired electrophysiological signals” (e.g., number of action potentials, amplitude, refractory period) can demonstrated physical proximity. For example, if two neurons have identical action potentials (i.e., amplitude, duration, refractory period) how does the ordinary artisan determine proximity without using non-electrophysiological signals (e.g., distance measurements). In addition, given the term “adjacent” encompasses neurons that are next to one another but remain physically separate from each other it is unclear how adjacent neurons can functionally have both similar and different oscillation patterns. Moreover, claim 19 is drawn to “similar” and “different” oscillation patterns. It is unclear when an oscillation pattern is considered “similar” or “different”
Conclusion
No claim 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.
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/H.A.P./Examiner, Art Unit 1644 /AMY E JUEDES/Primary Examiner, Art Unit 1644