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 .
Applicant's listing of claims filed on 04-18-2024 have been received and entered. Claims 1-19 are pending in the instant application.
Election/Restrictions
Applicant’s election of Group I (Claims 1-10) and the species of chronic heart
failure in the reply filed on 06-30-2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 11-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06-30-2026.
Regarding to claim 2, it is noted that applicants have elected the species of chronic heart failure while claim 2 is directed to liver disease and/or kidney disease. While claim 2 further limits the choices available for the method of claim 1 regarding the subject suffering from liver disease and/or kidney disease, they don’t recite language that limits the claimed methods to treatment of those specific conditions, and which excludes embodiments where the subject has chronic heart failure. Thus, claim 2 has been rejoined with the elected claims because claim 2 encompasses the elected species (e.g., where the subject has chronic heart failure).
Claims 1-10 and the species of chronic heart failure are under consideration.
Priority
This application is US application filed on 04/18/2024 that claims priority from US provisional application no 63/460,054 filed on 04/18/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10-14-2024 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112
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.
Claims 1-10 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.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304,312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The claims encompass a method of treating large number of genera of various diseases (about 2 pages of different genus of diseases and conditions). They represent different types of diseases or disorders that differ from each other physiologically and pathologically, and they have different pathological symptoms. Treatment of those different diseases or disorders is drawn to different scientific considerations and has to be considered individually.
Additionally, independent claim 1 encompasses a genus of any treatment module which activates the reward system of any subject, and claim 4 specifies that treatment module encompasses any sensory, any auditory, any visual and/or any chemical stimulation.
The instant disclosure exemplifies limited species for the large number of genera of various diseases as well as treatment modules to activate the brain's reward system (specifically the dopaminergic neurons in the ventral tegmental area (VTA)):
Stereotactic injection: Mice were randomly divided between VTA-activated and control group, and an AAV8 virus was used for Cre-dependent DREADD expression. 0.4 µl of the virus was injected into the right VTA of DAT-Cre mice. Control mice were injected with a sham AAV8-hSyn-DIO-mCherry construct, lacking the DREADD gene” (see instant disclosure pages 38-39).
Myocardial infarction - The left anterior descending (LAD) coronary artery permanent ligation was used as a model for acute myocardial infarction (Ml). Prior to the procedure (see instant disclosure page 39).
Example 1: Neuronal connection between the VTA and the liver: The liver produces proteins associated with better recovery following acute myocardial infarction (MI). The main focus was on brain regions involved in emotional processing due to the correlation between the emotional state and outcomes following acute MI. Cells in the VTA were also identified, a brain region mediating positively-valenced emotions, which have been linked to immune system function (Figures 4A-J) (see instant disclosure page 41-42).
Example2: VTA activation as treatment for myocardial infarction: To determine the effect of VTA activation on cardiac recovery following acute myocardial infarction (MI), a chemogenetic technique termed 'Designer Receptors Exclusively Activated by Designer Drugs' (DREADD) was used to directly activate dopaminergic neurons in the VTA in a mouse AMI model (Figure lA). These findings may provide at least a partial explanation for the differences in the cardiac functional outcomes observed between VTA-activated and control mice (see instant disclosure page 42-44).
Example3: VTA activation modifies expression of proteins associated with various diseases: To further investigate the processes that mediate the beneficial effects of VTA activation following MI, a time point of 4 days post-MI was selected, which serves as the interphase between the inflammatory and proliferative phases of MI and is considered as a key step in the process of wound healing. Protein levels that differed significantly between VTA-activated and control mice were mostly associated with cellular and metabolic types of processes. These proteins were also involved in intracellular signal transduction, regulatory processes, immune system function, structure formation, etc. (Figure 3B) (see instant disclosure page 44-45).
1. Using treatment module comprising any sensory, auditory, visual and/or chemical stimulation is unpredictable for treating large number of genera of various diseases: Aran et al (Journal of Affective Disorders 347 (2024) 557–567, DOI: 10.1016/j.jad.2023.11.068) teach “Across ages and places: Unpredictability of maternal sensory signals and child internalizing behaviors” (Title), and “Patterns of sensory inputs early in life play an integral role in shaping the maturation of neural circuits, including those implicated in emotion and cognition. In both experimental animal models and observational human research, unpredictable sensory signals have been linked to aberrant developmental outcomes, including poor memory and effortful control. These findings suggest that sensitivity to unpredictable sensory signals is conserved across species and sculpts the developing brain. The current study provides a novel investigation of unpredictable maternal sensory signals in early life and child internalizing behaviors….. Findings across the three diverse cohorts suggest that unpredictable maternal signals early in life shape the development of internalizing behaviors, particularly fearfulness and anxiety” (Abstract). Aran et al concluded that “The findings of the current study suggest that experiencing unpredictable maternal sensory signals during early life is linked to children’s emotional development, especially anxious phenotypes. Results of the current investigation support the accumulating evidence that unpredictability of sensory signals is an important form of adversity and documents its unique contribution to risk for internalizing disorders among children. Notably, unpredictable parenting behaviors can be seen as an actionable form of adversity that is amenable to early intervention. Unpredictable maternal signals therefore may be a biologically plausible target due to its effects on brain circuit maturation for the prevention and treatment of internalizing disorders in youth” (Page 564, right column).
2. The claims are also directed to treatment module activates a dopaminergic neuron in the ventral tegmental area (VTA) which is biologically heterogeneous which makes its activation using any treatment module for any subjects unpredictable: Gantz et al (Annu. Rev. Physiol. 2018. 80:219–41, Doi: 10.1146/annurev-physiol-021317-121615) teach “the population of neurons in the ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that the projections, neurochemistry, and receptor and ion channel expression in this cell population vary widely….. Although all dopamine neurons fire action potentials in a pacemaker pattern in the absence of synaptic input, the intrinsic properties that underlie this activity differ considerably. Likewise, the transition into a burst/pause pattern results from combinations of intrinsic ion conductances, inhibitory and excitatory synaptic inputs that differ among this cell population. Finally, synaptic plasticity is a key regulator of the rate and pattern of activity in different groups of dopamine neurons. Through these fundamental properties, the activity of dopamine neurons is regulated and underlies the wide-ranging functions that have been attributed to dopamine” (Abtract)
3. Individual subjects can have substantially different reward-system activation: Cohen et al (Cognitive Brain Research 25 (2005) 851– 861, Doi: doi:10.1016/j.cogbrainres.2005.09.018) teach “Psychologists have linked the personality trait extraversion both to differences in reward sensitivity and to dopamine functioning, but little is known about how these differences are reflected in the functioning of the brain’s dopaminergic neural reward system. Here, we show that individual differences in extraversion and the presence of the A1 allele on the dopamine D2 receptor gene predict activation magnitudes in the brain’s reward system during a gambling task. In two functional MRI experiments, participants probabilistically received rewards either immediately following a behavioral response (Study 1) or after a 7.5 s anticipation period (Study 2). Although group activation maps revealed anticipation- and reward-related activations in the reward system, individual differences in extraversion and the presence of the D2 Taq1A allele predicted a significant amount of inter-subject variability in the magnitudes of reward-related, but not anticipation-related, activations. These results demonstrate a link between stable differences in personality, genetics, and brain functioning” (Abstract). Cohen et al concluded that “Our findings demonstrate clear links between stable individual differences in personality, genetics, and functioning of the brain’s reward system. This anatomically and functionally interconnected network is critical for both biological and social survival, and our findings suggest that variation in the functioning of this system is linked with socially and emotionally relevant conditions. For example, both low extraversion scores and the DRD2 A1 allele have been linked to psychiatric disorders including depression, drug dependency, and compulsive gambling. Thus, an important question for future research is whether the relationships between individual differences in personality, genetics, and brain activation observed here might relate to clinical disorders and whether neuroimaging could be used to guide new approaches for diagnosis and treatment of such conditions” (Page 859, left column, 3rd para.)
4. Different stimulation parameters produce different dopamine responses: Weidner et al (Brain Stimulation 13 (2020) 363e371, Doi: 10.1016/j.brs.2019.11.005) teach “Matching stimulation paradigms resolve apparent differences between optogenetic and electrical VTA stimulation” (Title), and “electrical and optogenetic stimulation have been compared in several model systems, among them the mesolimbic dopamine system. Typically, large differences were found. Such differences could be explained by electrical stimulation leading to the release of glutamate from glutamatergic cells, which in contrast to the neuromodulator dopamine directly drives short-latency firing in the target regions. In addition, electrical stimulation could affect fibers from more posterior regions, passing close to the stimulated area or excite local GABAergic cells which in turn modulate the output of dopaminergic cells. A major challenge in answering these questions and adequately comparing electrical and optogenetic stimulation has always been the matching of both stimulation modalities: it is unclear to what extent the large differences previously described by us and other groups are due to the fundamentally different mode of action of both techniques or due to differences in strength between optogenetic and electrical stimulation. (Page 364, left column, 3rd -4th para.).
The specification lacks sufficient variety of species for each of various diseases/disorders genera to reflect the variance in for each of various diseases/disorders genera showing any treatment module can be used in treatment of any subject. The specification does not provide sufficient descriptive support for the myriad of variant embraced by the claims.
Overall, what these statements indicate is that the Applicant must provide adequate description of such various species for each of various diseases/disorders genera and various treatment module for various subject such that the Artisan of skill could determine the desired effects/functions of the claimed various culture condition/medium on various somatic cells. Hence, the analysis above demonstrates that Applicant has not determined the desired effects/functions of the broadly claimed various treatment module on treatment of various diseases/disorders genera for full scope of the claims.
The skilled artisan cannot envision the detailed compositions/functions of the encompassed any treatment module on treatment of various diseases/disorders genera other than those described in the specification, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of treatment. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of preparing/using it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v.Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Thus, it is concluded that the written description requirement is not satisfied for the claimed genus of any treatment module on treatment of various diseases/disorders genera.
Claim Rejections - 35 USC § 112
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.
Claims 1-10 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
A method of treating myocardial infarction in a subject in need thereof, the method comprising administering via injection a viral vector with designer receptors exclusively activated by designer drugs (DREADD) to a mammalian subject which activates a dopaminergic neuron in the ventral tegmental area (VTA) of said subject, thereby treating myocardial infarction (see the instant disclosure page 42: Example2: VTA activation as treatment for myocardial infarction)
does not reasonably provide enablement for
A method of treating various diseases listed in the claims’, wherein said disease is not cancer, in any subject in need thereof, the method comprising subjecting the subject via any administration route to any treatment module which activates any reward system of the subject, thereby treating the disease in the subject.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant's claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform "undue experimentation" to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.0l(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, applicant's claims are not enabled.
Nature of the invention:
A method of treating diseases, wherein said disease is not cancer, in a subject in need thereof, the method comprising subjecting the subject to a treatment module which activates the reward system of the subject, thereby treating the disease in the subject.
The breadth of the claims:
The claims are broadly directed to a method of treating various diseases, wherein said disease is not cancer, in any subject in need thereof, the method comprising subjecting the subject via any administration route to any treatment module which activates any reward system of the subject, thereby treating the disease in the subject.
It is noted that the claims broadly encompass treating any liver disease, kidney disease, psoriatic arthritis,… Alzheimer's disease, Parkinson's disease… They represent different types of diseases or disorders that differ from each other physiologically and pathologically, and they have different pathological symptoms. However, the instant disclosure does not exemplify method and/or mechanism that could be used in treatment applications other than treating myocardial infarction.
The working examples and guidance provided:
Stereotactic injection: Mice were randomly divided between VTA-activated and control group, and an AAV8 virus was used for Cre-dependent DREADD expression. 0.4 µl of the virus was injected into the right VTA of DAT-Cre mice. Control mice were injected with a sham AAV8-hSyn-DIO-mCherry construct, lacking the DREADD gene” (see instant disclosure pages 38-39). Myocardial infarction - The left anterior descending (LAD) coronary artery permanent ligation was used as a model for acute myocardial infarction (Ml). Prior to the procedure (see instant disclosure page 39). Example1: Neuronal connection between the VTA and the liver: The liver produces proteins associated with better recovery following acute myocardial infarction (MI). The main focus was on brain regions involved in emotional processing due to the correlation between the emotional state and outcomes following acute MI. Cells in the VTA were also identified, a brain region mediating positively-valenced emotions, which have been linked to immune system function (Figures 4A-J) (see instant disclosure page 41-42). Example2: VTA activation as treatment for myocardial infarction: To determine the effect of VTA activation on cardiac recovery following acute myocardial infarction (MI), a chemogenetic technique termed 'Designer Receptors Exclusively Activated by Designer Drugs' (DREADD) was used to directly activate dopaminergic neurons in the VTA in a mouse AMI model (Figure lA). These findings may provide at least a partial explanation for the differences in the cardiac functional outcomes observed between VTA-activated and control mice (see instant disclosure page 42-44). Example3: VTA activation modifies expression of proteins associated with various diseases: To further investigate the processes that mediate the beneficial effects of VTA activation following MI, a time point of 4 days post-MI was selected, which serves as the interphase between the inflammatory and proliferative phases of MI and is considered as a key step in the process of wound healing. Protein levels that differed significantly between VTA-activated and control mice were mostly associated with cellular and metabolic types of processes. These proteins were also involved in intracellular signal transduction, regulatory processes, immune system function, structure formation, etc. (Figure 3B) (see instant disclosure page 44-45).
The working examples provided by the specification do not correlate to preventing or treating any
disease other than VTA activation as treatment for myocardial infarction via a chemogenetic technique termed 'Designer Receptors Exclusively Activated by Designer Drugs' (DREADD) that was used to directly activate dopaminergic neurons in the VTA in a mouse AMI model. Given the lack of guidance provided by the specification it would have required undue experimentation for one of skill in the art to practice the invention as claimed without a reasonable expectation of success.
State of the Art and predictability of the Art:
The claims encompass treating various diseases by subjecting any subject via any administration route to any treatment module which activates any reward system of the subject. The claims encompass any subject such as human, monkey, chimpanzee, bovine, sheep, horse, dogs, cats, mice, rats, squirrels, prairie dogs, other rodents, whales, other mammals, fish, birds, insects, arthropods, reptiles and snakes etc., that differ from each other morphologically and physiologically (organisms like sponge or Jelly fish may not even have brain). The claims encompass any administration such as oral administration, intravenous administration, intraperitoneal administration, intrathecal administration, intramuscular administration, subcutaneous administration, topical administration, inhalation, intradermal administration, intravitreal injection, and intraventricle administration etc. that face various barriers before a gene therapy (gene/viral vector) can reach its target site. Thus, it is unpredictable for subjecting any subject via any administration route to any treatment module that can activates reward system in the subject.
1. The activation/prediction of reward system is unpredictable because of heterogeneity of the reward system:
de Jong et al (Annu. Rev. Neurosci. 2022. 45:109–29, doi: 10.1146/annurev-neuro-110920- 011929) teach that “Ventral tegmental area (VTA) dopamine (DA) neurons are often thought to uniformly encode reward prediction errors. Conversely, DA release in the nucleus accumbens (NAc), the prominent projection target of these neurons, has been implicated in reinforcement learning, motivation, aversion, and incentive salience. This contrast between heterogeneous functions of DA release versus a homogeneous role for DA neuron activity raises numerous questions regarding how VTA DA activity translates into NAc DA release. Further complicating this issue is increasing evidence that distinct VTA DA projections into defined NAc subregions mediate diverse behavioral functions. Here, we evaluate evidence for heterogeneity within the mesoaccumbal DA system and argue that frameworks of DA function must incorporate the precise topographic organization of VTA DA neurons to clarify their contribution to health and disease.” (Abstract). de Jong et al teach summary points: 1. The midbrain dopamine (DA) system is highly heterogeneous from the molecular composition and anatomical organization of DA neurons to the function of projection defined DA systems in behavior. 2. Whether DA release and the firing activity of DA neurons are dissociable is a topic of current debate. 3. Aversion-excited DA neurons have distinct projections and physiological characteristics, are located in the medial ventral tegmental area, and appear to belong to a unique class. 4. Defining DA neurons with respect to their striatal target refines their role in behavior (page 122). de Jong et al discuss future issues: 1. How can we integrate reward, motivation, and aversion encoding within different DA subsystems into a coherent framework of DA function? 2. What is the functional consequence of DA signaling in defined striatal territories, and how are these altered by experience or in disease? 3. Why is reward prediction error signaling so prominent both within the activity of DA neurons and in DA release in their target regions, and what is the significance of such a signal? 4. Should we consider DA neurons as performing individualized computations or as populations or subpopulations that collectively encode metrics critical for behavior? 5. Do DA neurons generate model-based computations, and if so, what inputs onto DA neurons support model-free versus model-based behaviors? 6. Are the mechanisms that govern local control of DA release conserved throughout the striatum? 7. Is ramping of DA release generated at the axon terminal, or does ramping arise from ramping activity of dopamine cell bodies? (page 122).
Lerner et al (Current Opinion in Neurobiology 2021, 67:123–130, Doi: 10.1016/j.conb.2020.10.012) teach “Dopamine neurons of the ventral tegmental area (VTA) have been intensely studied for their role in reinforcement learning. These dopamine neurons encode reward prediction error (RPE) – the difference between predicted and received rewards. ……Recent progress in dopamine research has led to stronger formulations of the RPE hypothesis, which have refined the theory while largely confirming the initial observation. However, it remains a challenge to incorporate other hypothesized functions of dopamine, for example in motivation and motor behavior, into the RPE hypothesis. Whether dopamine’s functions can indeed be united under one theory is not clear: many recent studies have also brought attention to previously underappreciated dopamine neuron diversity. This diversity – in gene expression, intrinsic currents, synaptic connectivity, and neurotransmitter co-release – could give rise to a diversity of functions not amenable to description under one theory” (Page 123, left to right column). Lerner et al concluded that “we must also better understand how dopamine signals in distinct subsets of neurons are being generated by upstream circuits and interpreted by downstream circuits. On the former problem, input mapping studies have led the way but a good deal of work is left to describe the detailed mechanisms by which these inputs contribute to the encoding properties of dopamine neurons, as well as to understand how such connectivity might be altered by sex, across development and aging, and in conditions (e.g., stress) that are related to the emergence of psychiatric conditions. On the latter problem, we are only beginning to understand the transformations that take place between dopamine cell body activity, axon activity, and neurotransmitter release. The astoundingly complex axonal arbors of midbrain dopamine neurons provoke many questions about how action potential propagation is regulated. Complex neuromodulatory mechanisms are known to regulate dopamine release at terminals. Different release machinery can regulate dopamine release on different time scales, and yet further mechanisms may regulate the differential co-release of other neurotransmitters. Thus, even when we observe RPE signals while recording dopamine neuron action potentials at cell bodies, we may question whether and in what form downstream circuits are receiving these signals. As researchers tackle these difficult questions in the coming years, theories of dopamine function will, no doubt, again need to be updated” (Page 127, left to right column)
2. Mammalian “reward system” cannot simply to be assumed to exist or to function in the same way in lower organisms. In some species, particular components of the reward system are specifically reported as absent, uncertain, or substantially different:
Dvoracek et al (Neuroscience and Biobehavioral Reviews 123 (2021) 301–319, Doi: 10.1016/j.neubiorev.2020.12.032) teach Drosophila reward system: “The fruit fly Drosophila melanogaster brain is the most extensively investigated model of a reward system in insects. Drosophila can discriminate between rewarding and punishing environmental stimuli and consequently undergo associative learning. Functional models, especially those modelling mushroom bodies, are constantly being developed using newly discovered information, adding to the complexity of creating a simple model of the reward system. This review aims to clarify whether its reward system also includes a hedonic component. Neurochemical systems that mediate the ‘wanting’ component of reward in the Drosophila brain are well documented, however, the systems that mediate the pleasure component of reward in mammals, including those involving the endogenous opioid and endocannabinoid systems, are unlikely to be present in insects. The mushroom body components exhibit differential developmental age and different functional processes. We propose a hypothetical hierarchy of the levels of reinforcement processing in response to particular stimuli, and the parallel processes that take place concurrently. The possible presence of activity-silencing and meta-satiety inducing levels in Drosophila should be further investigated” (Abstract). Dvoracek et al teach that “A number of behavioural studies conducted in Drosophila clearly confirm that the fly mushroom body network is capable of associative learning, although the detailed mechanism remains unclear. One of the prerequisites for associative learning is the ability to discriminate the appetitive from the aversive — which, however, is also requirement of the reward function. On the other hand, this ability does not necessarily imply the presence of the reward itself as we assume it in mammals, including the hedonic component. Further, it is possible to imagine associations caused by different mechanisms: a simple ‘learning’ mechanism of a single cell, an association mechanism inseparable from network properties, or a mechanism of support of associative processes by a secondary system. This system may utilise DA or another neurotransmitter and may allow/initiate/strengthen the associations without being a direct bearer of the reward. Another mechanism may utilise a system conveying information about generalized satiety, satisfaction, and reward in the sense of ’liking’; in this form, reward could already be a form of abstract operation. We suppose that further investigation of the insect reward function might provide more evidence of the ‘liking’ function, probably based on different neurochemical systems than in mammals” (Page 315, left column, 3rd para.).
Sovik et al (Chapter 6, Advances in Insect Physiology, Volume 48, ISSN 0065-2806, Doi: 10.1016/bs.aiip.2014.12.006) teach “Insect reward systems: comparing flies and bees” (title), and “we consider current knowledge about reward pathways in the two predominant insect models: Drosophila melanogaster and the honeybee Apis mellifera. These two models are phylogenetically distantly related and have vastly different ecologies: fruit flies are mostly solitary while honeybees live in complex societies involving social foraging and brood care. Initially, it was assumed the reward system was essentially similar between these two organisms, but more recent studies have appeared to highlight quite significant differences. Here, we critically evaluate apparent differences in the neurobiology of the reward system between these organisms. We discuss which differences may be real and which may be reflective of the very different modes of analysis applied in these two models. Finally, we discuss how modification of reward systems might have contributed to social evolution in insects” Sovik et al teach “The study of reward systems in insects was inspired by a landmark study, demonstrating that the activation of a single identified neuron could replace sucrose reward during conditioning in honeybees (Apis mellifera). Since this pivotal study, a range of studies have examined different aspects of rewards in insects and have attempted to pinpoint the neural substrates responsible. From these studies, there appeared to be quite significant differences between the results from insects and the more established understanding of the physiology of reward in mammals. In mammals, dopamine (DA) systems emerged as key neurochemical signals for rewards, while in insects octopamine (OA) systems were considered to signal rewards. OA and DA are chemically quite similar, but OA is only a trace amine in mammalian nervous systems.” (Page 190).
3. The claims also read on treating various disease using treatment module (instant disclosure provide example for viral vector) for delivery to activate the reward system via various administration routes in vivo. The administration route can include subcutaneous, intravenous, intramuscular, intrathecal, intraganglionic, intraneural, intraventricular, intraperitoneal, oral, topical, dermal, transdermal, inhalation, and intranasal administration etc. The state of the prior art of gene transfer and gene therapy was not well developed and was highly unpredictable before the effective filing date of the claimed invention. While progress has been made in recent years for gene transfer in vivo, vector targeting desired tissues in vivo continues to be unpredictable and inefficient as supported by numerous teachings available in the art. There are many factors that contribute to the unpredictability of gene transfer or gene therapy in vivo.
Kotterman et al (Nature Reviews, Vol. 15, p. 445-451, doi: 10.1038/nrg3742) reports that AAV still has significant challenges regarding successful use in treatment regimens (pg. 450 col. 2). Specifically, Kotterman points out “widespread natural exposure to AAVs has resulted in a large portion of the population with neutralizing antibodies specific to capsids in the blood and other body fluids, which markedly limit gene delivery by many natural vectors... following cellular transduction, AAV capsid epitopes can become cross-presented on major histocompatibility complex (MHC) class I molecules, which leads to the elimination of transduced cells by capsid specific cytotoxic T lymphocytes and the corresponding loss of gene expression". “For systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue. A vector that gains access to an organ, or that is directly administered to that organ, can then encounter numerous transport barriers to efficient transduction of the often-large tissue volumes involved in disease, including cell bodies and intervening extracellular matrix to which many AAV variants bind". “The surface of a target cell may lack the primary and/or secondary receptors that are necessary for vector binding and internalization. Furthermore, endosomal escape, proteasomal escape, nuclear entry and vector unpackaging all represent barriers to transduction" (e.g., p. 447, under BOX 1).
Shim et al (Current Gene Therapy, Vol. 17, No. 5, p. 1-18, DOI: 10.2174/1566523218666180119121949) reports that in all gene therapy applications, delivery issues are essential, and nucleic acids are highly polar macromolecules and cannot diffuse through cell membranes. For the delivery of nucleic acids into target cells, viral and nonviral methods have been used. Despite success, viral vectors still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems (e.g., p. 1, right column, 2nd paragraph). “Although nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of “delivery”, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release… Behavior in the physiological environment is the most important hurdle for vectors” (e.g., p. 13, left column, 4th full paragraph). Thus, viral vector delivery of nucleic acid still suffers from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al (NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The ideal vector would be cell type specific, but the design of either non-viral or viral vectors that successfully target a specific cellular receptor has been elusive despite a great deal of effort. To date, re-engineered viral vectors are often too large, too unstable, or otherwise unable to reach the nucleus of some cell types. Non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (e.g., p. 10, under “Scientific Hurdles”). For viral vectors, especially adenoviral and adeno-associated viral vectors, the exposed individuals have circulating antibodies that can interfere with transduction of closely related recombinant vectors. The control of an unanticipated immune response can be complicated by the challenge of "turning off" expression of transgene driven by constitutive, non-conditioned promoter sequence specifically designed to always be "on" (e.g., p. 11, 1st paragraph).
Bulcha et al (Signal Transduction and Targeted Therapy, 6:53, p. 1-24, https://doi.org/10.1038/s41392-021-00487-6) discusses “Viral vector platforms within the gene therapy landscape” (e.g., Title). Bulcha et al report the challenges of rAAV vector for gene therapy include immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. In fact, the immune system will always be a major barrier for any gene therapy approach. The adaptive immunity to the capsid and the foreign transgene represents major factors for decreased efficacy (e.g., p. 14, bridging left column and right column). “Mechanisms for innate immunity have been well-described in response to viruses, but exploration of innate immune response towards AAV vectors is understudied… In addition, evidence is accumulating for the possibility that the AAV vector genome can elicit an innate immune response, necessitating an area of research that is critically needed” (e.g., p. 14, right column, 2nd full paragraph). “Finally, a challenge that must be confronted is managing the right treatment doses, which may be at the heart of the strong immunological responses and subsequent toxicities seen in recent trials… These studies and others indicate that further evaluation of the appropriate routes of administration, capsid choice, and vector genome designs are still needed, even for approved drugs” (e.g., Bridging, p. 14, right column and p. 15, left column).
It is apparent that for systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue, and there is immune response against adenovirus vector and AAV vector. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The challenges of rAAV vector for gene therapy include immunogenicity towards the vector remain the largest challenge for AAV-based gene therapies. The adaptive immunity to the capsid and the foreign transgene represents major factors for decreased efficacy. The AAV vector genome can elicit an innate immune response, necessitating an area of research that is critically needed. Further evaluation of the appropriate routes of administration, capsid choice, and vector genome designs are still needed, even for approved drugs.
The amount of experimentation necessary:
One skilled in the art before the effective filing date of the claimed invention would require, to prepare a treatment module such viral vector to activate the reward system of any subject, and in vivo administering the treatment module such viral vector to various subjects carrying treatment module comprising sensory, auditory, visual and/or chemical stimulation for treating various types of diseases, trial and error experimentation to determine the presence of the viral vector at the target cells in the various subject carrying the treatment module such as viral vector, administered via various administration routes, trial and error experimentation to determine whether the treatment module such as viral vector are expressed at the target cells with sufficient level, trial and error experimentation to determine whether there is off-target effects on the subject suffering various diseases, and trial and error experimentation to determine whether the pathological symptoms of the various diseases in the subject have been ameliorated by the treatment of the treatment module.
For the reasons discussed above, it would have required undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice over the full scope of the invention claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art.
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.
Claims 1-4, 6-7, 10 are rejected under 35 U.S.C. 103 as being unpatentable over Rolls et al (Pub. No.: US 2020/0246329 Al, Pub. Date: Aug. 6, 2020) (applicants’ own work) in view of Ichim et al (Pub. No .: US 2022/0202860 A1, Pub. Date: Jun . 30, 2022).
Claim interpretation:
The instant specification teaches that “Chemical stimulation may be effected for example by a dopamine agonist capable of crossing the blood brain barrier. Non-limiting examples of dopamine agonists include Cocaine, Heroin, L-dopa, Lisuride, Adamantane, Amino tetralin, Benzazepine, Ergoline, Dihydrexidine derivative, …” (Page 14, lines 1-11). Thus, dopamine agonists as listed such as Lisuride, Adamantane …... are interpreted as chemical stimulation, and capable of crossing the blood brain barrier.
Regarding to claims 1, 3, Rolls et al teach “A method for modulating an immune response by activating or inhibiting dopaminergic neurons in the Ventral Tegmental Area (VTA) is provided. Modulation is achieved by modulating the activity, the abundance or both of: a natural killer cell, a CD8 T-cell, a CD4 T-cell, a B-cell, a dendritic cell, a macrophage, a granulocyte, or their combination” (Abstract). Rolls et al teach “FIGS. 6A-6G. Demonstrates the DREADD-mediated activation of VTA dopaminergic neurons system. FIG. 6A shows a schematic demonstration of experimental design. The viral construct used for ere-dependent expression of DREADDs and mCherry, is shown. The control construct does not contain the information for DREADDs” ([0021], page 3)
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Although Rolls et al teach method for modulating an immune response which is achieved by modulating the activity, the abundance or both of immune cells (abstract) and “an immune response is associated with a disease and a method described herein is used to optimize the immune response according to the exact condition” ([0037], page 5), Rolls et al do not teach treating chronic heart failure. Ichim et al cure the deficiency.
Ichim et al teach “a method of preventing, and/or inhibiting, and /or reversing heart failure, and/or post infarct pathological remodeling comprising the steps of: a) identifying a patient suffering from heart failure and/or a patient having undergoing a myocardial infarct; b) extracting from said patient immune cells; c) contacting said immune cells with regenerative cells in a manner so that regenerative cells endow onto said immune cells properties capable of inhibiting and/or reversing heart failure ; and d) administering said immune cells into said patient” ([0020], page 3). Ichim et al teach “The immunomodulatory properties of reprogrammed immune cells may be used in treating a wide variety of disorders, dysfunctions and diseases, such as those that, intrinsically, as a secondary effect or as a side effect of treatment, present with deleterious immune system processes and effects” ([0107], page 17) and “Reprogrammed immune cells modulate immune responses….”([0110], page 17).
It is noted that Rolls et al also teach modulating an immune response via activation of VTA: stimulation to the dopaminergic neurons in the Ventral Tegmental Area (VTA), is modulating the activity, the abundance or both of: a natural killer cell, a CD8 T-cell, a CD4 T-cell, a B-cell, a Dendritic cell, or any combination thereof ([0065], page 8). Rolls et al also teach activating an immune response can be achieved by activating dopaminergic neurons in the Ventral Tegmental Area (VTA) of the subject, and the activating is increasing the number of: NK cells, B-cells and dendritic cells in the subject's spleen, is inducing the level of CD62L in CD8 T-cells, is inducing migration of CD8 T-cells ([0066], page 8). Additionally, Ichim et al teach “treatment of heart failure with immune modulatory cells” ([0002] page 1) such as T regulatory cell expresses CD62 ligand (see page 8, item 252 of [0020]). Ichim et al also expressly describe use with immunomodulatory agents: “Other agents that can be used in conjunction with reprogrammed immune cells, in transplantation therapies in particular, include immunomodulatory agents” ([0109], page 17). Thus, one of ordinary skill in the art would have been motivated to combine the teachings of prior arts to apply modulating an immune response by activating or inhibiting dopaminergic neurons in the Ventral Tegmental Area (VTA) as taught by Rolls et al to treat heart failure as taught by Ichim et al.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify and apply modulating an immune response by activating or inhibiting dopaminergic neurons in the Ventral Tegmental Area (VTA) as taught by Rolls et al to treat heart failure as taught by Ichim et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Ichim et al teach the use of immunomodulatory agents to treat heart failure: “Other agents that can be used in conjunction with reprogrammed immune cells, in transplantation therapies in particular, include immunomodulatory agents” ([0109], page 17). Ichim et al teach “The immunomodulatory properties of reprogrammed immune cells may be used in treating a wide variety of disorders, dysfunctions and diseases, such as those that, intrinsically, as a secondary effect or as a side effect of treatment, present with deleterious immune system processes and effects” ([0107], page 17) and “Reprogrammed immune cells modulate immune responses….”([0110], page 17). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Rolls et al provides experimental evidence that VTA dopaminergic neuron manipulation produces changes in peripheral immune cells population and functions and Ichim et al teach that immune cell manipulation can be used therapeutically in heart failure and post-infarct cardiac failure.
Regarding to claim 2, it is noted that applicants have elected the species of chronic heart failure while claim 2 is directed to liver disease and/or kidney disease. Claim 2 is included in the instant rejection because of the reasons described above in the “Election/Restrictions”.
Regarding to claim 4, Rolls et al teach chemical stimulation: “immune response is a dopamine agonist. In another embodiment, the dopamine agonist is Lisuride. In another embodiment, a dopamine agonist is an Adamantane……” ([0051], page 6).
Regarding to claim 6, Rolls et al teach “… activation of VTA neurons can be performed by a pharmacologic agent, a magnetic and/or an electric stimulation, an ultrasound, or any combination thereof” ([0049]. Page 2).
Regarding to claim 7, Rolls et al teach “In another embodiment, VTA neurons are activated by synthetic ligand (RASSLs). In another embodiment, VTA neurons are activated by transfecting VTA neurons with designer receptors exclusively activated by designer drug (DREADDs) …...” ([0050], page 6).
Regarding to claim 10, Rolls et al teach “In another embodiment, a modulator of an immune response or a compound that activates VTA neurons is a compound that is blood-brain-barrier (BBB) permeable. In another embodiment, a modulator of an immune response or a compound that activates VTA neurons is a compound that can penetrate the BBB, by itself or via a carrier….” ([0048], page 6). Rolls et al teach “immune response is a dopamine agonist. In another embodiment, the dopamine agonist is Lisuride. In another embodiment, a dopamine agonist is an Adamantane……” ([0051], page 6).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Rolls et al (Pub. No.: US 2020/0246329 Al, Pub. Date: Aug. 6, 2020) (applicants’ own work) in view of Ichim et al (Pub. No .: US 2022/0202860 A1, Pub. Date: Jun . 30, 2022) as applied to claims 1-4, 6-7, 10 above and further in view of Lorenz et al (Front. Hum. Neurosci., 04 February 2015, 10.3389/fnhum.2015.00040).
The teachings of Rolls et al and Ichim et al above are incorporated herein in their entirety.
The above references do not teach treatment modules comprises digital experiences and/or virtual reality stimulation. Lorenz et al cure the deficiency.
Regarding to claim 5, Lorenz et al teach “video game training and the reward system” (title)and “we conducted a longitudinal study to explore reward-related functional predictors in relation to video gaming experience as well as functional changes in the brain in response to video game training. Fifty healthy participants were randomly assigned to a video game training (TG) or control group (CG). Before and after training/control period, functional magnetic resonance imaging (fMRI) was conducted using a non-video game related reward task. …... We suggest that video games are able to keep striatal responses to reward flexible, a mechanism which might be of critical value for applications such as therapeutic cognitive training.” (Abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references and apply the digital experiences such as video game training as taught by Lorenz et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Lorenz et al teach “Due to the high use, video games have come into the research focus of disciplines such as psychology and neuroscience. It has been shown that training with video games can lead to improvement in cognitive performance” (page 1, left column, last para.) and “We believe that video games are able to keep striatal responses to reward flexible, a mechanism which might be extremely important to keep motivation high, and thus might be of critical value for many different applications, including cognitive training and therapeutic possibilities” (Page 8, left column, last para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Lorenz et al were successful in using video games to keep striatal responses to reward flexible to keep motivation high.
Claim 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Rolls et al (Pub. No.: US 2020/0246329 Al, Pub. Date: Aug. 6, 2020) (applicants’ own work) in view of Ichim et al (Pub. No .: US 2022/0202860 A1, Pub. Date: Jun . 30, 2022) as applied to claims 1-4, 6-7, 10 above and further in view of Hendler et al (WO 2020/178820 A1, International Publication Date: 10 September 2020) (applicant’s own work).
The teachings of Rolls et al and Ichim et al above are incorporated herein in their entirety.
The above references do not teach treatment modules that comprise neurofeedback. Hendler et al cure the deficiency.
Regarding to claim 8, Hendler et al teach “neurofeedback and induction of an immune response” (title) and “The present invention is directed to a method for inducing an immune response in a subject, including a step of activating neurons in the mesolimbic network of the subject by applying a neurofeedback” (Abstract)
Regarding to claim 9, Hendler et al teach “the neurofeedback comprises electroencephalography (EEG), functional magnetic resonance imaging (fMRI), or a combination thereof.” ([010], page 2)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references and apply the neurofeedback for inducing an immune response as taught by Hendler et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Hendler et al teach “Biofeedback can train people to consciously regulate autonomic functions such as heart rate, skin conductance, and bowel and bladder function, and has even allowed individuals to modulate higher-level unconscious biological processes such as pain, athletic performance, and anxiety. The training of brain activity or connectivity, i.e., brain functionality, by means of biofeedback, is termed neurofeedback (NF)” ([004], page 1) and “the use of fMRI neurofeedback may improve the correspondence between first-person experience and specific brain activation patterns in a manner that minimally affects the experience itself. In some embodiments, the use of fMRI provides meditators the ability to enhance their control over their own brain activity” ([064], page 11). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Hendler et al were successful in using neurofeedback to induce of an immune response.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
