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 .
2. Applicant’s response filed on 03/02/2026 is acknowledged.
3. Claims 1-21 are pending. Claims 1, 3, 1-11 and 17 are independent claims.
4. Applicant’s election of Group I and the species of SEQ ID NO:3, AAV, neuron and chronic pain in the reply filed on 03/02/2026 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)).
5. Claims 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim.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 03/02/2026.
6. Applicant’s IDS document filed on 03/02/2026 has been considered.
7. Claims 1-19 are currently under consideration as they read on the species of the nucleic acid of SEQ ID NO:3, the AAV vector, the neuron cell and method for treating chronic pain. The Examiner extended the search to the nucleic acids of SEQ ID NOs 6 and 11.
8. 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.
9. Claims 1-19 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: in vivo methods of applying ultrasound to a cell expressing a polypeptide selected from the group consisting of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24, the specification does not reasonably provide enablement for:
a method of inducing cation influx in a cell, the method comprising: expressing in the cell a polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-like; wherein the polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and applying ultrasound to the cell, thereby inducing cation influx in the cell of claim 1; wherein the cell is sensitized to mechanical deformation or stretch caused by ultrasound and/or wherein the application of ultrasound effects a change in mechanosensory polypeptide conductance in the cell and activates or modifies cell activity or function of claim 2; a method of rendering a cell responsive to mechanical deformation or stretch caused by ultrasound or sensitizing a cell to mechanical deformation or stretch caused by ultrasound and activating and/or modifying activity or function of the cell, the method comprising: (a) transducing a cell to express a heterologous, bacterial mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; (b) applying ultrasound to the cell; and (c) inducing cation influx in the bacterial mechanosensory polypeptide expressing cell and an alteration in cell activity and/or function following the application of ultrasound, thereby rendering the cell responsive to mechanical deformation or stretch caused by ultrasound of claim 3; wherein the polynucleotide sequence encoding the bacterial mechanosensory polypeptide is codon-optimized for expression in a mammalian or human cell and is non-naturally occurring of claim 4; wherein the heterologous, bacterial mechanosensory polypeptide is expressed in the cell following transduction of the cell by a plasmid or viral vector which contains the polynucleotide sequence encoding polypeptide of claim 5; wherein the cell is transduced by a viral vector selected from a lentivirus vector or an adeno-associated virus (AAV) vector of claim 6; wherein the cell is one or more of a muscle cell, a cardiac muscle cell, an insulin secreting cell, a glial cell, or a neuronal cell of claim 7; wherein the neuronal cell is selected from a motor neuron, a sensory neuron, an interneuron, or an Agouti-Related Protein-expression positive (AGRP-tve) neuron of claim 8; wherein the ultrasound has a frequency of about 0.2 MHz to about 20 MHz and/or has a focal zone of about 1 cubic millimeter to about 1 cubic centimeter of claim 9; a method of treating a disease or disorder in a subject in need thereof, the method comprising:(i) expressing in a cell of a mammalian subject a heterologous nucleic acid molecule encoding a mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and (ii) applying ultrasound to the cell, thereby treating the disease or disorder in the subject of claim 10; a method of treating a disease or disorder in a mammalian subject in need thereof or modulating neuronal activity or function in a subject in need thereof, the method comprising: (i) transducing into a cell of the subject a polynucleotide molecule encoding an exogenous, bacterial mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; (ii) applying ultrasound to the cell; and (iii) inducing cation influx in the bacterial mechanosensory polypeptide-expressing cell and an alteration in cell activity and/or function following the application of ultrasound, thereby treating the disease or disorder in the subject of claim 11; wherein the cell is one or more of a muscle cell, a cardiac muscle cell, an insulin secreting cell, a glial cell, or a neuronal cell of claim 12; wherein the cell is a neuronal cell of claim 13; wherein the neuronal cell is selected from a motor neuron, a sensory neuron, an interneuron, or an Agouti-Related Protein-expression positive (AGRP-tve) neuron of claim 14; wherein the ultrasound is applied to the cell in
the hypothalamus of the subject of claim 15; wherein the disease or disorder is a neurological
disease or disorder, or a neural circuit disease selected from Parkinson's disease, depression, muscle weakness, muscle atrophy, muscle degeneration obsessive-compulsive disorder, eating disorders, chronic pain, epilepsy, spinal injury, anxiety, Alzheimer's, post-traumatic stress disorder (PTSD), or cervical spinal cord injury or muscle weakness, muscle atrophy, muscle degeneration, spinal injury, or cervical spinal cord injury of claim 16; a method of distal modulation of neuronal activity in a subject in need thereof, the method comprising: (i) expressing in a neuronal cell of a mammalian subject a heterologous nucleic acid molecule encoding a mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and (ii) applying ultrasound to the neuronal cell at a first site in the subject's nervous system and modulating the activity of neuronal cells at a second site in the subject's nervous system; wherein the second site is distal to the first site of claim 17; wherein the neuronal cells are selected from brain neuron cells, hippocampal neuron cells, or motor neurons of claim 18; and wherein the first site is the spinal cord and the second site is muscle tissue downstream of the first site of claim 19. The specification disclosure does not enable one skilled in the art to practice the invention without an undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 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, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification discloses in vivo methods of applying ultrasound to a cell expressing a polypeptide selected from the group consisting of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24 encoded by the full length nucleic acids of SEQ ID NOs 3, 6, 9, 11, 14, 17, 20, 23 and 26.
The terms “comprising” and “encodes” are open-ended and expand the nucleic acid sequences encompassed to include additional non disclosed nucleic acids outside of the region encoding the proteins of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24. The resulting amino acid sequences may also include additional amino acids. The instant method is only enabled for use with SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24, not variants or fragments thereof comprising additional non-related sequence.
Without sufficient guidance, the changes which can be made in the instantly recited nucleic acid sequences and still encode a polypeptide that maintains the functional properties is unpredictable, as is the identity of which subsequences would encode a functional polypeptide; thus the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue.
The positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The instant claims do not require that the nucleic acids encode full length sequences of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24; but rather encompasses any subsequences thereof. The specification does not provide sufficient guidance as to which subsequences would hybridize under stringent conditions to SEQ ID NOs 3, 5, 8 and 11. The specification does not provide any working examples of any subsequences that would exhibit the claimed functions for use in the claimed invention. Thus it would require undue experimentation of the skilled artisan to determine which subsequences would have the function of the full length molecules and of the subsequences that are encompassed.
Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function.
There is insufficient guidance in the specification as filed as to how the skilled artisan would make the various nucleic acids and polypeptides recited in the instant claims. A person of skill in the art would not know which sequences are essential, which sequences are non-essential, and what particular sequence lengths identify essential sequences. There is insufficient guidance to direct a person of skill in the art to select particular sequences or sequence lengths as essential for the claimed functions. Without detailed direction as to which nucleic acid sequences are essential to the function of the encoded polypeptide, a person of skill in the art would not be able to determine without undue experimentation which of the plethora of polynucleotide, polypeptide and fragment sequences encompassed by the instant claims would exhibit the claimed functional characteristics, other than the nucleic acids of SEQ ID NOs 3, 6, 9, 11, 14, 17, 20, 23 and 26 encoding the polypeptide sequences of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24.
The art acknowledges that function cannot be predicted based solely on structural similarity to a protein found in the sequence databases and recognized that it was unpredictable if any functional activity will be shared by two polypeptides having less than 100% identity over the full length of their sequences. In particular, the art of Friedberg et al. (PTO-892; Reference U) discusses annotation transfer by sequence similarity, also known as homology-based transfer may not be very reliable for functional annotation even in high-alignment identity percentages (In particular, page 227, whole document). Mao et al. (PTO-892; Reference V) teaches that “the earliest protein function prediction methods were based on homology, such as BLAST (Basic Local Alignment Search Tool). However, these methods have several limitations, such as the fact that proteins with similar sequences do not necessarily have similar functions, and vice versa. Even functionally similar proteins may have different sequences. These methods fail to fully account for the complexity of protein attributes and their actual functions when calculating similarity, leading to deficiencies in considering related variables.”(In particular, page 1, whole document).
Thus, it is highly unpredictable if any functional activity will be shared by two polypeptides having less than 100% identity over the full length of their sequences.
In view of this unpredictability; the skilled artisan would not reasonably expect a polypeptide having anything less than 100% identity over the full length of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and 24, to share the same functions Thus, the recitation of partial nucleic acid sequences and variations in sequences to SEQ ID NOs 3, 6, 9, 11, 14, 17, 20, 23 and 26, in the absence of a testable function does not allow the skilled artisan to make and use the encoding nucleic acids commensurate in scope with the instant claims without undue experimentation. The specification does not provide sufficient guidance as to which amino acids may be substituted, deleted, inserted and/or added and still retain the requisite function.
The language in claims 1-19 is open language that opens up the recited nucleic acids to include any number of undisclosed nucleotides added onto either end of the nucleic acid molecules. As written, the claims encompass an enormous number of undisclosed nucleic acids that may include unrelated sequence.
The instant claims encompass subsequences. The specification does not provide sufficient guidance as to which nucleic acids subsequences would encode functional polypeptides. The specification does not adequately disclose the genus of functional nucleic acid subsequences for use in the claimed invention. Thus, it would require undue experimentation of the skilled artisan to determine which subsequences, would have the function of the full length molecules. There is insufficient support in the specification for any and all nucleic acid subsequences of SEQ ID NOs 3, 6, 9, 11, 14, 17, 20, 23 and 26.
The specification is not enabled for the functions of a “inducing cation influx in a cell” “rendering a cell responsive to mechanical deformation or stretch caused by ultrasound or sensitizing a cell to mechanical deformation or stretch caused by ultrasound and activating and/or modifying activity or function of the cell”; “treating a disease or disorder in a subject in need thereof”; “treating a disease or disorder in a mammalian subject in need thereof or modulating neuronal activity or function in a subject in need thereof”
“wherein the disease or disorder is a neurological disease or disorder, or a neural circuit disease selected from Parkinson's disease, depression, muscle weakness, muscle atrophy, muscle degeneration obsessive-compulsive disorder, eating disorders, chronic pain, epilepsy, spinal injury, anxiety, Alzheimer's, post-traumatic stress disorder (PTSD), or cervical spinal cord injury or muscle weakness, muscle atrophy, muscle degeneration, spinal injury, or cervical spinal cord injury” and “distal modulation of neuronal activity in a subject in need thereof” using the genus of non-enabled nucleic acids, polypeptides encoded and cells comprising which are encompassed by the claims.
Since no in vivo studies were performed, it is not clear that the claimed therapeutic strategy would treat any of the recited diseases. The specification does not adequately teach how to effectively treat or arrive at any therapeutic endpoint in animals, much less to treat the genus of diseases and disorders encompassed, by performing the claimed method. The specification does not teach how to extrapolate data obtained from the in vitro studies to the development of effective in vivo animal therapeutic treatment, commensurate in scope with the claimed invention.
Substantiating evidence may be in the form of animal tests, which constitute recognized screening procedures with clear relevance to efficacy in humans. See Ex parte Krepelka, 231 USPQ 746 (Board of Patent Appeals and Interferences 1986) and cases cited therein. Ex parte Maas, 9 USPQ2d 1746. It is not enough to rely on in vitro studies where, as here, a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to efficacy in humans or animals (emphasis added). Ex parte Maas, 9 USPQ2d 1746.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
10. Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Applicant is in possession of: in vivo methods of applying ultrasound to a cell expressing a polypeptide selected from the group consisting of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 and
Applicant is not in possession of: a method of inducing cation influx in a cell, the method comprising: expressing in the cell a polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-like; wherein the polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and applying ultrasound to the cell, thereby inducing cation influx in the cell of claim 1; wherein the cell is sensitized to mechanical deformation or stretch caused by ultrasound and/or wherein the application of ultrasound effects a change in mechanosensory polypeptide conductance in the cell and activates or modifies cell activity or function of claim 2; a method of rendering a cell responsive to mechanical deformation or stretch caused by ultrasound or sensitizing a cell to mechanical deformation or stretch caused by ultrasound and activating and/or modifying activity or function of the cell, the method comprising: (a) transducing a cell to express a heterologous, bacterial mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; (b) applying ultrasound to the cell; and (c) inducing cation influx in the bacterial mechanosensory polypeptide expressing cell and an alteration in cell activity and/or function following the application of ultrasound, thereby rendering the cell responsive to mechanical deformation or stretch caused by ultrasound of claim 3; wherein the polynucleotide sequence encoding the bacterial mechanosensory polypeptide is codon-optimized for expression in a mammalian or human cell and is non-naturally occurring of claim 4; wherein the heterologous, bacterial mechanosensory polypeptide is expressed in the cell following transduction of the cell by a plasmid or viral vector which contains the polynucleotide sequence encoding polypeptide of claim 5; wherein the cell is transduced by a viral vector selected from a lentivirus vector or an adeno-associated virus (AAV) vector of claim 6; wherein the cell is one or more of a muscle cell, a cardiac muscle cell, an insulin secreting cell, a glial cell, or a neuronal cell of claim 7; wherein the neuronal cell is selected from a motor neuron, a sensory neuron, an interneuron, or an Agouti-Related Protein-expression positive (AGRP-tve) neuron of claim 8; wherein the ultrasound has a frequency of about 0.2 MHz to about 20 MHz and/or has a focal zone of about 1 cubic millimeter to about 1 cubic centimeter of claim 9; a method of treating a disease or disorder in a subject in need thereof, the method comprising:(i) expressing in a cell of a mammalian subject a heterologous nucleic acid molecule encoding a mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and (ii) applying ultrasound to the cell, thereby treating the disease or disorder in the subject of claim 10; a method of treating a disease or disorder in a mammalian subject in need thereof or modulating neuronal activity or function in a subject in need thereof, the method comprising: (i) transducing into a cell of the subject a polynucleotide molecule encoding an exogenous, bacterial mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; (ii) applying ultrasound to the cell; and (iii) inducing cation influx in the bacterial mechanosensory polypeptide-expressing cell and an alteration in cell activity and/or function following the application of ultrasound, thereby treating the disease or disorder in the subject of claim 11; wherein the cell is one or more of a muscle cell, a cardiac muscle cell, an insulin secreting cell, a glial cell, or a neuronal cell of claim 12; wherein the cell is a neuronal cell of claim 13; wherein the neuronal cell is selected from a motor neuron, a sensory neuron, an interneuron, or an Agouti-Related Protein-expression positive (AGRP-tve) neuron of claim 14; wherein the ultrasound is applied to the cell in
the hypothalamus of the subject of claim 15; wherein the disease or disorder is a neurological
disease or disorder, or a neural circuit disease selected from Parkinson's disease, depression, muscle weakness, muscle atrophy, muscle degeneration obsessive-compulsive disorder, eating disorders, chronic pain, epilepsy, spinal injury, anxiety, Alzheimer's, post-traumatic stress disorder (PTSD), or cervical spinal cord injury or muscle weakness, muscle atrophy, muscle degeneration, spinal injury, or cervical spinal cord injury of claim 16; a method of distal modulation of neuronal activity in a subject in need thereof, the method comprising: (i) expressing in a neuronal cell of a mammalian subject a heterologous nucleic acid molecule encoding a mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and (ii) applying ultrasound to the neuronal cell at a first site in the subject's nervous system and modulating the activity of neuronal cells at a second site in the subject's nervous system; wherein the second site is distal to the first site of claim 17; wherein the neuronal cells are selected from brain neuron cells, hippocampal neuron cells, or motor neurons of claim 18; and wherein the first site is the spinal cord and the second site is muscle tissue downstream of the first site of claim 19
There is no correlation between the structure of the genus of nucleic acids, polypeptides, and cells comprising the polypeptide and the functions of be usable for “inducing cation influx in a cell” “rendering a cell responsive to mechanical deformation or stretch caused by ultrasound or sensitizing a cell to mechanical deformation or stretch caused by ultrasound and activating and/or modifying activity or function of the cell”; “treating a disease or disorder in a subject in need thereof”; “treating a disease or disorder in a mammalian subject in need thereof or modulating neuronal activity or function in a subject in need thereof” “wherein the disease or disorder is a neurological disease or disorder, or a neural circuit disease selected from Parkinson's disease, depression, muscle weakness, muscle atrophy, muscle degeneration obsessive-compulsive disorder, eating disorders, chronic pain, epilepsy, spinal injury, anxiety, Alzheimer's, post-traumatic stress disorder (PTSD), or cervical spinal cord injury or muscle weakness, muscle atrophy, muscle degeneration, spinal injury, or cervical spinal cord injury” and “distal modulation of neuronal activity in a subject in need thereof”.
Applicant has disclosed only in vivo methods of applying ultrasound to a cell expressing a polypeptide selected from the group consisting of SEQ ID NOs 1, 4, 7, 10, 12, 15, 18, 21 encoded by the full length nucleic acid molecules of SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26; therefore, the skilled artisan cannot envision all the contemplated nucleic acid polypeptide and method possibilities recited in the instant claims. Consequently, conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
The specification has not adequately described nucleic acids, polypeptide and cells thereof with the functions of a “inducing cation influx in a cell” “rendering a cell responsive to mechanical deformation or stretch caused by ultrasound or sensitizing a cell to mechanical deformation or stretch caused by ultrasound and activating and/or modifying activity or function of the cell”; “treating a disease or disorder in a subject in need thereof”; “treating a disease or disorder in a mammalian subject in need thereof or modulating neuronal activity or function in a subject in need thereof” “wherein the disease or disorder is a neurological disease or disorder, or a neural circuit disease selected from Parkinson's disease, depression, muscle weakness, muscle atrophy, muscle degeneration obsessive-compulsive disorder, eating disorders, chronic pain, epilepsy, spinal injury, anxiety, Alzheimer's, post-traumatic stress disorder (PTSD), or cervical spinal cord injury or muscle weakness, muscle atrophy, muscle degeneration, spinal injury, or cervical spinal cord injury” and “distal modulation of neuronal activity in a subject in need thereof” using the genus of non-enabled nucleic acids, polypeptides encoded and cells comprising which are encompassed by the claims.
Adequate written description requires more than a mere statement that it is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC1993). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
11. 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.
Independent claims
Claim 1: a method of inducing cation influx in a cell, the method comprising: expressing in the cell a polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-like; wherein the polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and applying ultrasound to the cell, thereby inducing cation influx in the cell.
Claim 3: a method of rendering a cell responsive to mechanical deformation or stretch caused by ultrasound or sensitizing a cell to mechanical deformation or stretch caused by ultrasound and activating and/or modifying activity or function of the cell, the method comprising: (a) transducing a cell to express a heterologous, bacterial mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; (b) applying ultrasound to the cell; and (c) inducing cation influx in the bacterial mechanosensory polypeptide expressing cell and an alteration in cell activity and/or function following the application of ultrasound, thereby rendering the cell responsive to mechanical deformation or stretch caused by ultrasound
Claim 10: a method of treating a disease or disorder in a subject in need thereof, the method comprising:(i) expressing in a cell of a mammalian subject a heterologous nucleic acid molecule encoding a mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and (ii) applying ultrasound to the cell, thereby treating the disease or disorder in the subject.
Claim 11: a method of treating a disease or disorder in a mammalian subject in need thereof or modulating neuronal activity or function in a subject in need thereof, the method comprising: (i) transducing into a cell of the subject a polynucleotide molecule encoding an exogenous, bacterial mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; (ii) applying ultrasound to the cell; and (iii) inducing cation influx in the bacterial mechanosensory polypeptide-expressing cell and an alteration in cell activity and/or function following the application of ultrasound, thereby treating the disease or disorder in the subject
Claim 17: a method of distal modulation of neuronal activity in a subject in need thereof, the method comprising: (i) expressing in a neuronal cell of a mammalian subject a heterologous nucleic acid molecule encoding a mechanosensory polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MscSfam, or MscS-Like; wherein the mechanosensory polypeptide is encoded by a polynucleotide sequence having at least 85% sequence identity to a polynucleotide sequence selected from SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 23 or SEQ ID NO: 26, respectively; and (ii) applying ultrasound to the neuronal cell at a first site in the subject's nervous system and modulating the activity of neuronal cells at a second site in the subject's nervous system; wherein the second site is distal to the first site.
12. 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.
13. Claims 1-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020/142415 (PTO-892; Reference N) as evidenced by the attached sequence alignment.
WO 2020/142415 teaches E. coli MscL (EcMscL) channel activity can be induced in HEK cells (model for excitatory cells such as neuron and cardiac cells) by ultrasound stimulation. HEK293 cells were cultured in standard DMEM growth media on multi-electrode array (MEA) petri dishes and a lipofection agent was used to transfect the cells with plasmid DNA. The MEA plate was placed on an ultrasound device and was set up to record electrical signals from all electrodes simultaneously. Therefore, any channel activity in cells attached to an electrode would lead to a spike in the electrical signal from that electrode. Ultrasound stimulation (Pulse width: 250 ms, Repetition rate: 2 Hz, Frequency: 1.1 MHz) was used to stimulate the cells on the MEA plate. The electrical recordings show a spike in signal on some electrodes after ultrasound stimulation [Fig. 14B] The results of the experiment confirm that MscL channel activity can be stimulated by ultrasound. Thus, heterologously expressed mechanosensitive channels, such as bacterial mechanosensitive channels or their generated site-directed mutants, in neurons are activated by internal or external mechanical stimuli, for modulating activities in dormant neurons in order to recover from coma, and persistent vegetative state. Thus, heterologously expressed mechanosensitive channels, or their generated site-directed mutants, in neurons can be activated by internal or external mechanical stimuli, for modulating neural activities in order to repair injury such as concussion, enhance neural regeneration, accelerated learning and memory processing. Efficiency of such external stimulation process can be enhanced with or without conjugation of nanoprobes, wherein the device providing external mechanical force or magnetic field can be controlled to tune the duration, frequency and strength of stimulation. This will allow control on molecular delivery, stimulation or cellular death leading to the desired therapeutic outcome (In particular, paragraph [00125], Example 12, claims, whole document)
The reference teaches that the MscL gene from the BL21 (DE3) Escherichia coli strain, which encodes for a 136 amino acid monomer, was retrieved and codon optimized for mammalian cell expression and wherein an Adeno-associated virus (AAV) compatible plasmid DNA construct, encoding the MscL gene and a TM-specific promoter, leads to the expression of MscL in TM cells. The reference teaches wherein the said mechanosensitive channel (e.g., MscL) is delivered through viral vectors or non-viral methods (In particular, paragraph [0076], claims, whole document)
The reference teaches a method wherein heterologously expressed mechanosensitive channels, such as bacterial mechanosensitive channels (MscL, MscS, MscK, MscG) or their generated site-directed mutants, are used for stimulation of cells, including neurons, cardiac and muscle cells for treatment and prevention diseases including but not limited to, neurological diseases such as pain, epilepsy, stroke as well as cardiovascular diseases and muscular dystrophies. (In particular, paragraph [0091], claims, whole document)
The reference teaches reference SEQ ID NO:1 which is encoded by instant SEQ ID NO:6 and reference SEQ ID NOs 5 and 6 which are encoded by instant SEQ ID NO:11.
The reference teachings anticipate the claimed invention.
14. No claim is allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner' s supervisor, Misook Yu, can be reached at telephone number (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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April 3, 2026
/Nora M Rooney/
Primary Examiner, Art Unit 1641