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 .
DETAILED ACTION
Status of Application/Election/Restrictions
2. Claims 1-20 are pending in this application and under examination in this office action.
Claim Objections
3. Claims 1 and 11 are objected to because of the following informalities: The limitation “comprising exogenous nucleic acid encoding….and exogenous nucleic acid encoding….” recited in claims 11 and 11 is objected to because an article “an” between the limitation “comprising” and the limitation “exogenous” is missing. Appropriate correction is required.
Claim Rejections - 35 USC § 112
4. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1-20 are indefinite because:
i. Claims 1 and 11 recite the limitation "the number" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
ii. The limitation “cardiac arrest or severe hypotension (shock)” recited in line 3 of the claims 3 and 13 is unclear. It is unclear whether the limitation “(shock)” within the parenthesis following the phrase “cardiac arrest or severe hypotension” is part of the claimed invention. Thus, the claims are indefinite.
iii. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
5. 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 1-20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 1-20 encompass using a genus of exogenous nucleic acid encoding a genus of NeuroD1 polypeptide, a genus of exogenous nucleic acid encoding a genus of biologically active fragment of NeuroD1, a genus of exogenous nucleic acid encoding a genus of Dlx2 polypeptide and a genus of exogenous nucleic acid encoding a genus of biological active fragment of Dlx2 for generating new glutamatergic neuron or new GABAergic and glutamatergic neurons, increasing survival of GABAergic neurons or GABAergic and glutamatergic neurons, generating new non-reactive astrocytes, or reducing the number of reactive astrocytes.
Applicant has not disclosed sufficient species for the broad genus of NeuroD1 polypeptide including variants and the broad genus of biologically active fragment of NeuroD1 including variants, the broad genus of Dlx2 polypeptide including variants, the broad genus of biological active fragment of Dlx2 polypeptide including variants.
The specification only describes the nucleic acid sequence of SEQ ID NO:1 or 3, or AAV5-CAG-flex-ND1-GFP or AAV9-1.6 kb-GFAP-cre with flex-ND1-mCherry encoding NeuroD1 comprising the amino acid sequence of SEQ ID NO:2 or 4; and the nucleic acid sequence of SEQ ID NO: 10 or 12, or AAV5-CAG-flex-Dlx2-GFP or AAV9-1.6 kb-GFAP-cre with flex-Dlx2-mCherry encoding Dlx2 comprising the amino acid sequence of SEQ ID NO:11 or 13 (Examples 2-6, Figures 2-8). However, the claims are not limited to using a polynucleotide or an expression vector encoding NeuroD1 of SEQ ID NO:2 or 4 and a polynucleotide or an expression vector encoding Dlx2 of SEQ ID NO:10 or 12 set forth above but also encompass using structurally and functionally undefined polynucleotide variants encoding structurally and functionally undefined NeuroD1 and Dlx2 variants and structurally and functionally undefined biological active fragments thereof in the claimed method in view of the specification (see [0069]-[0071]; [0085]; [0128]-[0136] based on the published application)
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, it is clear that Applicant is in possession of using the nucleic acid sequence of SEQ ID NO:1 or 3, or AAV5-CAG-flex-ND1-GFP or AAV9-1.6 kb-GFAP-cre with flex-ND1-mCherry encoding NeuroD1 comprising the amino acid sequence of SEQ ID NO:2 or 4, and the nucleic acid sequence of SEQ ID NO: 10 or 12, or AAV5-CAG-flex-Dlx2-GFP or AAV9-1.6 kb-GFAP-cre with flex-Dlx2-mCherry encoding Dlx2 comprising the amino acid sequence of SEQ ID NO:11 or 13 for generating new glutamatergic neurons and/or new GABAergic neurons or generating new non-reactive astrocytes in the claimed method (Examples 2-6, Figures 2-8). However, Applicant is not in possession of using other structurally and functionally undefined polynucleotide variants encoding structurally and functionally undefined NeuroD2 variants and structurally and functionally undefined polynucleotide variants encoding Dlx2 variants, and structurally and functionally undefined biological active fragments thereof in the claimed method.
Based on paragraphs [0070]-[0072]; [0084]-[0087]; [0103]; [0106]-[0107]; [0131]-[0134] of the published specification, the definition of “NeuroD1 protein” also encompasses variants of NeuroD1 having at least 75% identity to SEQ ID NO:2 or 4, the definition of “NeuroD1 nucleic acid” also encompasses NeuroD1 nucleic acids having at least 70% identity to SEQ ID NO: 1 or 3, and the definition of “Dlx2 protein” also encompass variants of Dlx2 having at least 75% identity to SEQ ID NO: 11 or 13 and the definition of “Dlx2 nucleic acid” also encompasses Dlx2 nucleic acids having at least 70% identity to SEQ ID NO:10 or 12. Thus, the claims also encompass using structurally and functionally undefined polynucleotide variants having at least 70% sequence identity to SEQ ID NO:1 or 3 encoding structurally and functionally undefined NeuroD1 variants having at least 75% identity to SEQ ID NO:2 or 4 and structurally and functionally undefined polynucleotide variants having at least 70% sequence identity to SEQ ID NO: 10 or 12 encoding Dlx2 variants having at least 75% identity to SEQ ID NO: 11 or 13, and structurally and functionally undefined biological active fragments thereof in the claimed method. The specification fails to provide sufficient descriptive information as to what other polynucleotide variants of SEQ ID NO: 1 or 3 encoding NeuroD1 including variants are, what other NeuroD1 variants are, what other polynucleotide variants of SEQ ID:10 or 12 encoding Dlx2 including variants are and what other Dlx2 variants are, and whether these variants can be used in the claimed method because a single amino acid change on a molecule or protein can abolish the activity or binding ability of the molecule or protein. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138). Although many amino acid substitutions are possible in any given protein, the position of where such amino acid substitutions can be made is critical for maintaining the function of a protein; i.e. only certain positions can tolerate conservative substitutions without changing the relationship of three dimensional structure and function of the protein (col 2, p. 1306, Bowie et al. Science, 1990, 247:1306-1310). Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452). Alaoui-lsmaili teaches that designing a mutein having predictable activities is difficult because of the complexity of the interactions between ligands and receptors (Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507). For example, given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking (see p. 502, right col., 2th paragraph). Further, when multiple mutations are introduced, there is even less predictability because Guo et al. teaches that the effects of mutations on protein function are largely additive (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210). Applicant fails to teach what other structures/amino acid sequences can or cannot be included/changed in polynucleotide variants having at least 70% identity to SEQ ID NO:1 or 3 or NeuroD1 variants having at least 75% identity to SEQ ID NO:2 or 4 in order to preserve the activity of NeuroD1 of SEQ ID NO:2 or 4 in generating new GABAergic and/or glutamatergic neurons, and what other structures/amino acid sequences can or cannot be included/changed in polynucleotide variants having at least 70% identity to SEQ ID NO:10 or 12 or Dlx2 variants having at least 75% identity to SEQ ID NO: 11 or 13 in order to preserve the activity of Dlx2 of SEQ ID NO:11 or 13 in generating new GABAergic and/or glutamatergic neurons.
The specification provides no identification of any particular portion of the structure that must be conserved. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of NeuroD1 variants and Dlx2 variants and biologically active fragments of NeuroD1 and Dlx2. There is no description of the conserved regions which are critical to the function of the genus claimed. There is no description of the sites at which variability may be tolerated and there is no information regarding the relation of the structure of other NeuroD1 variants and Dlx2 variants and biologically active fragments of NeuroD1 and Dlx2 to the function of NeuroD1 of SEQ ID NO:2 or 4 and Dlx2 of SEQ ID NO:11 or 13. Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other NeuroD1 variants and Dlx2 variants and biologically active fragments of NeuroD1 and Dlx2 might be. Since the common characteristics/features of other NeuroD1 variants and Dlx2 variants and biologically active fragments of NeuroD1 and Dlx2 are unknown, a skilled artisan cannot envision the functional correlations of the claimed genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of NeuroD1, the genus of Dlx2 and the genus of biologically active fragments of NeuroD1 and Dlx2.
Based on MPEP § 2161.01 and §2163, “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”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of NeuroD1, the genus of Dlx2 and the genus of biologically active fragments of NeuroD1 and Dlx2, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed methods have not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
6. 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 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.
Claim Rejections - 35 USC § 103
7. 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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Chen’373 (US2017/0239373, published Aug 24, 2017, priority Feb 18, 2016; issued as US10973930 on Apr 13, 2021) in view of Chen’599 (US2014/0024599, published Jan 23, 2014, priority Jul 19, 2012; issued as US10561742) and Zhu et al. (US20120301446).
Claims 1-10 are drawn to a method for (1) generating new glutamatergic neuron or new GABAergic and glutamatergic neurons, (2) increasing survival of GABAergic neurons or GABAergic and glutamatergic neurons, (3) generating new non-reactive astrocytes, or (4) reducing the number of reactive astrocytes, in a mammal having had a hemorrhagic stroke and in need of (1), (2), (3), or (4), wherein said method comprises administering a composition comprising exogenous nucleic acid encoding a NeuroD1 polypeptide or a biologically active fragment thereof and exogenous nucleic acid encoding a Dlx2 polypeptide or a biologically active fragment thereof to said mammal. Dependent claims are directed to wherein the mammal is a human (claim 2), wherein the hemorrhagic stroke is caused by different conditions including ischemic stroke, physical injury; tumor; inflammation; infection; global ischemia as caused by cardiac arrest or severe hypotension (shock); hypoxic-ischemic encephalopathy as caused by hypoxia, hypoglycemia, or anemia; meningitis; and dehydration; or a combination of any two or more thereof (claim 3), delivering the expression vectors encoding a NeuroDI polypeptide and a Dlx2 polypeptide or biologically active fragments thereof to the location of the hemorrhagic stroke in the brain and a recombinant viral expression vector including an adeno-associated virus expression vector (AAV) (claims 4-6), a stereotactic intracranial injection (claim 7), further comprising administering the exogenous nucleic acid encoding a NeuroD1 polypeptide or a biological active fragment thereof and exogenous nucleic acid encoding a Dlx2 polypeptide or a biological active fragment thereof on one expression vector including a recombinant viral vector or a recombinant AVV (claim 8), wherein the composition about 1-500uL of a pharmaceutically acceptable carrier containing AAV at a concentration of 1010-1014 AAV particles/ml of carrier comprising a nucleic acid encoding a NeuroD1 polypeptide or a biologically active fragment thereof and a nucleic acid encoding a Dlx2 polypeptide or a biologically active fragment thereof (claim 9), wherein the composition is injected in the brain at a controlled flow rate of about 0.1-5L/min (claim 10).
Chen’373 (US2017/0239373) teaches a method for generating GABAergic neurons in a living mammal’s brain comprising administering a composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to said mammal, which are related to instant claims 1-20 (see paragraphs [0030]-[0042]; [0046]-[0048]; [0068]-[0075], example 1; [0076]-[0078] Examples 2-3, p. 14, claims 1-20.). Chen’373 also teaches the mammal is a human as in claims 2 and 12 (see abstract; [0004]; [0007];[0009]; [0030]-[0031]; [0041]). Chen’373 teaches delivering the expression vectors encoding a NeuroDI polypeptide and a Dlx2 polypeptide or biologically active fragments thereof to the brain and a recombinant viral expression vector including an adeno-associated virus expression vector (AAV) as related to claims 4-6 and 14-16) via a stereotactic intracranial injection as in claims 7 and 17(see [0059]; [0009]; [0040]). Chen’373 teaches further comprising administering the exogenous nucleic acid encoding a NeuroD1 polypeptide and exogenous nucleic acid encoding a Dlx2 polypeptide on one expression vector including a recombinant viral vector or a recombinant AVV as in claims 8 and 18 (see paragraphs [0009]; [0056]-[0057]; [0059]; [0069]-[0078]). Chen’373 teaches injection of AAV using a 5ul syringe and a 34G needle in a volume of 2ul at a concentration of 1.4x1012-1.6x1012 GC/ml at a flow rate of 0.2ul/min (see paragraphs [0057] and [0059]), which are within the limitations recited in claims 9-10 and 19-20 (i.e. about 1-500uL, at a concentration of 1010-1014 AAV particles/ml and at a controlled flow rate of about 0.1-5uL/min).
But Chen’373 does not teach that the mammal has a hemorrhagic stroke or different conditions causing hemorrhagic stroke, including ischemic stroke, physical injury; tumor; inflammation; infection; global ischemia caused by cardiac arrest or severe hypotension; hypoxic-ischemic encephalopathy as caused by hypoxia, hypoglycemia, or anemia; meningitis; and dehydration; or a combination of any two or more thereof as in claim 3.
While Chen’373 does not teach that the mammal has a hemorrhagic stroke or different conditions causing the hemorrhagic stroke, Chen’599 (US2014/0024599) and Zhu et al. (US20120301446) teach these limitations and provide motivation and an expectation of success in generating new glutamatergic neuron and/or new GABAergic and glutamatergic neurons in the mammal with a hemorrhagic stroke including hemorrhagic stroke caused by different conditions, or administering within 3 days of the hemorrhagic stroke.
Chen’599 (US2014/0024599) teaches a method of treating a neurological condition including brain injury, brain tumor, stroke, focal ischemic stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a nucleic acid molecule encoding NeuroD1 to produce glutamatergic and GABAergic neurons, thereby to ameliorate the neurological condition including stroke, focal ischemic stroke of the subject, wherein the nucleic acid encoding NeuroD1 is delivered by a viral vector via intracerebral injection, spinal cord injection and/or injection into the cerebrospinal fluid or other administration routes including intravenous injection and intraperitoneal injection.(see paragraphs [0055], [0108]-[0109]; [0158]-[0166], examples 13-14; [0172]-[0173], example 17; examples 10-11; examples 12 & 15-17, claims 1-20). Chen’599 teaches that neurons are often killed or injured as a result of an injury or neurological condition including stroke, and that glial cells become reactive following brain or spinal cord injury or after a stroke (see paragraph [0004]). Chen’599 teaches converting astrocytes including reactive astrocytes and/or NG2 into glutamatergic and GABAergic neurons by expression of exogenous NeuroD1 in astrocytes and converting human astrocytes into GABAergic and Glutamatergic neurons by expression of exogenous Dlx2 in cultured human astrocytes (see paragraphs [0055], [0172]-[0173], examples 10-11; examples 16-17, claims 1-20). Chen’599 teaches administering to a nucleic acid molecule including a recombinant viral vector and an adeno-associated vector (AAV) encoding NeuroD1 to produce glutamatergic and GABAergic neurons an animal model of a neurodegenerative disease including brain injury, brain tumor, stroke, focal ischemic stroke, Alzheimer’s disease to convert astrocytes including reactive astrocytes and/or NG2 into glutamatergic and GABAergic neurons (see paragraphs [0108]-[0109]). Chen’599 also teaches converting human astrocytes into GABAergic and Glutamatergic neurons in cell culture by exogenous expression of Dlx2 in cultured human astrocytes (see paragraphs [0055]; [0172], Example 16).
Zhu et al. (US20120301446) teaches a method of treating a neurological condition including ischemic stroke, hemorrhagic stroke, brain injury in a subject in need thereof, comprising administering to the subject a composition comprising a transducible material comprising an effector domain which is a transcription factor polypeptide including NeuroD1 and/or DIx2 (Abstract; paragraphs [0040]; [0055]; [0056]-[0060]; [0066]-[0070]; [0072]-[0073]; [0078]-[0079], [0100]-[0102], Example 4, claims 1-39). Zhu teaches therapeutically effective dose of a nucleic acid molecule encoding NeuroD1 to produce glutamatergic and GABAergic neurons, thereby to ameliorate the neurological condition including ischemic stroke, hemorrhagic stroke, brain injury of the subject (see [0040]; [0055]-[0060]; [0072]; [0078]-[0079]). Zhu also teaches re-programming glial cells/astrocytes into neurons by His-DIx2-11R protein alone (see paragraphs [0029]; [0072]; [0100]-[0102], Example 4).
A person of ordinary skill in the art would have recognized that selecting and applying the known technique of generating glutamatergic and GABAergic neurons and converting astrocytes including reactive astrocytes into glutamatergic and GABAergic neurons by expression of exogenous NeuroD1 and exogenous Dlx2 in patients with brain injury or ischemic stroke or hemorrhagic stroke disclosed by Chen’599 and Zhu to the method of Chen’373 would have yielded the predictable result of generating GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a living mammal’s brain having had a hemorrhagic stroke and resulted in rescuing neuron loss or damages caused by hemorrhagic stroke.
Administration of a composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to a living mammal having had a hemorrhagic stroke would generate new GABAergic and/or glutamatergic neurons from astrocytes or reduce the number of reactive astrocytes in a living mammal’s brain having had a hemorrhagic stroke and result in rescuing neuron loss or damages caused by hemorrhagic stroke to alleviate the damage caused by hemorrhagic stroke in the mammal.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention was made to combine the teachings of Chen’599 and Zhu with the teaching of Chen’373 to modify the method of Chen’373 by administering to the living mammal’s brain a composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to generate new GABAergic and/or glutamatergic neurons from astrocytes or reduce the number of reactive astrocytes in the living mammal having had a hemorrhagic stroke and thereby rescue neuronal damage and loss caused by hemorrhagic stroke, in light of the teachings of Chen’599 and Zhu.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of generating glutamatergic and GABAergic neurons from astrocytes and converting astrocytes including reactive astrocytes into glutamatergic and GABAergic neurons by expression of exogenous NeuroD1 and exogenous Dlx2 in patients with brain injury or ischemic stroke or hemorrhagic stroke disclosed by Chen’599 and Zhu to the method of Chen’373 to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke.
Claim Rejections - 35 USC § 103
8. Claims 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chen’373 (US2017/0239373; issued as US10973930) in view of Chen’599 (US2014/0024599; issued as US10561742) and Zhu (US20120301446) as applied claims 1-10 above, and further in view of Miller et al. (US2011/0207828, published Aug 25, 2011, priority Aug 26, 2009).
Chen’373, Chen’599 and Zhu are set forth above and teach the limitations recited in claims 12-20 as set forth above.
But Chen’373, Chen’599 and Zhu do not teach that the administration of the claimed composition is within 3 days of the hemorrhagic stroke as recited in claim 11.
Miller et al. (US2011/0207828) teaches that treatment of stroke including ischemic stroke and hemorrhagic stroke requires medication as soon as possible and preferably within a few hours, such as less than 12, 8, 6, 4, or 2 or 1 hour; or a few days such as about 1, about 2 or about 3 days (see paragraphs [0067];[0069]-[0072]; [0027]; [0043]-[0044]; [0064];).
A person of ordinary skill in the art would have recognized that applying the known technique of administering medication for treatment of stroke including ischemic stroke and hemorrhagic stroke within 3 days disclosed by Miller to the method of Chen’373, Chen’599 and Zhu would have yielded the predictable result of generating GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a living mammal’s brain having had a hemorrhagic stroke and resulted in rescuing neuron loss or damages caused by hemorrhagic stroke.
Administration of the claimed composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to a living mammal having had a hemorrhagic stroke within 3 days of the hemorrhagic stroke would generate new GABAergic and/or glutamatergic neurons from astrocytes or reduce the number of reactive astrocytes in a living mammal’s brain having had a hemorrhagic stroke and result in rescuing neuron loss or damages caused by hemorrhagic stroke to alleviate the damage caused by hemorrhagic stroke in the mammal.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention was made to combine the teaching of with the teachings of Chen’373, Chen’599 and Zhu to modify the method of Chen’373, Chen’599 and Zhu by administering to the living mammal’s brain a composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to generate new GABAergic and/or glutamatergic neurons from astrocytes or reduce the number of reactive astrocytes in the living mammal having had a hemorrhagic stroke within 3 days of the hemorrhagic stroke, and thereby rescue neuronal damage and loss caused by hemorrhagic stroke, in light of the teaching of Miller.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of administering medication for treatment of stroke including ischemic stroke and hemorrhagic stroke within 3 days disclosed by Miller to the method of Chen’373, Chen’599 and Zhu to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke.
Double Patenting
9. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10973930 in view of in view of Chen’599 (US2014/0024599; issued as US10561742), Zhu et al. (US20120301446) and Miller et al. (US2011/0207828).
Claims 1-11 of the ‘930 patent claim a method for generating GABAergic neurons in a striatum of a living mammal’s brain from astrocytes, comprising administering to the astrocytes within the striatum a nucleic sequence encoding NeuroD1 polypeptide and a nucleic acid sequence encoding a Dlx2 polypeptide, wherein the nucleic acid sequence encoding the NeuroD1 polypeptide is operably linked to an astrocyte promoter, wherein the nucleic acid sequence encoding the NeuroD1 polypeptide or the nucleic acid sequence encoding Dlx2 polypeptide is administered to the astrocytes in the form of a viral vector including adeno-associated viral vector.
While the claims 1-11 of the ‘930 patent do not recite that the mammal has a hemorrhagic stroke as in instant claims 1 and 11 or different conditions causing hemorrhagic stroke in instant claims 3 and 13, Chen’599 and Zhu teach these limitations and provide motivation and an expectation of success for the reasons set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention was made to combine the teachings of Chen’599 and Zhu with the teaching of the claims of the ‘930 patent to modify the method of the ‘930 patent by administering to the living mammal’s brain a composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to generate new GABAergic and/or glutamatergic neurons from astrocytes or reduce the number of reactive astrocytes in the living mammal having had a hemorrhagic stroke and thereby rescue neuronal damage and loss caused by hemorrhagic stroke, in light of the teachings of Chen’599 and Zhu.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of generating glutamatergic and GABAergic neurons from astrocytes and converting astrocytes including reactive astrocytes into glutamatergic and GABAergic neurons by expression of exogenous NeuroD1 and exogenous Dlx2 in patients with brain injury or ischemic stroke or hemorrhagic stroke disclosed by Chen’599 and Zhu to the method of the ‘930 patent to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke.
In addition, while the claims 1-11 of the ‘930 patent do not recite administering within 3 days of the hemorrhagic stroke as in claim 11, Miller teaches this limitation and provides motivation and an expectation of success for the reasons set forth above. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention was made to combine the teaching Miller of with the teachings of the claims of the ‘930 patent, Chen’599 and Zhu to modify the method of the ‘930 patent, Chen’599 and Zhu by administering to the living mammal’s brain a composition comprising an exogenous nucleic acid encoding a NeuroD1 polypeptide and an exogenous nucleic acid encoding a Dlx2 polypeptide to generate new GABAergic and/or glutamatergic neurons from astrocytes or reduce the number of reactive astrocytes in the living mammal having had a hemorrhagic stroke within 3 days of the hemorrhagic stroke, and thereby rescue neuronal damage and loss caused by hemorrhagic stroke, in light of the teaching of Miller.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of administering medication for treatment of stroke including ischemic stroke and hemorrhagic stroke within 3 days disclosed by Miller to the method of the ‘930 patent, Chen’599 and Zhu to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke.
Double Patenting
10. Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No.9717804 or claims 1-19 of U.S. Patent No. 10201619 in view of Chen’373 (US2017/0239373; issued as US10973930), Chen’599 (US2014/0024599; issued as US10561742), Zhu et al. (US20120301446, as in IDS) and Miller et al. (US2011/0207828).
Claims 1-4 of the ‘804 patent claim a method of treating a neurological condition in a subject in need thereof comprising administering to the subject an expression vector encoding NeuroD1, wherein the neurological condition is characterized by loss of neurons and presence of reactive astrocytes and includes an injury to the CNS and stroke.
Claims 1-19 of the ‘619 patent encompass a method of treating a neurological condition in a subject in need thereof comprising administering to the subject an expression vector encoding NeuroD1, wherein the neurological condition is characterized by loss of neurons and presence of reactive NG2 cells and includes an injury to the CNS and stroke.
While the claims of the ‘804 patent or the claims of the ‘619 patent do not teach the use of a nucleic sequence encoding NeuroD1 polypeptide in combination with a nucleic acid sequence encoding a Dlx2 polypeptide and do not teach hemorrhagic stroke or administering within 3 days of the hemorrhagic stroke, Chen’373, Chen’599, Zhu and Miller teach these limitations for the reasons set forth above. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of generating glutamatergic and GABAergic neurons from astrocytes and converting astrocytes including reactive astrocytes into glutamatergic and GABAergic neurons by expression of exogenous NeuroD1 and exogenous Dlx2 in patients with brain injury or ischemic stroke or hemorrhagic stroke disclosed by Chen’373, Chen’599 and Zhu to the method of the ‘804 patent or the ‘619 patent to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke. It would also have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of administering medication for treatment of stroke including ischemic stroke and hemorrhagic stroke within 3 days disclosed by Miller to the method of the ‘804 patent Chen’373, Chen’599 and Zhu, or the method of the ‘619 patent, Chen’373, Chen’599 and Zhu to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke.
Double Patenting
11. Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 and 27 of copending Application No. 19/684917 in view of Chen’373 (US2017/0239373; issued as US10973930), Chen’599 (US2014/0024599; issued as US10561742), Zhu et al. (US20120301446) and Miller et al. (US2011/0207828).
Claims 1-25 and 27 of copending Application No. 19/684917 claim a method of treating the effects of disruption of normal blood flow in the CNS in an individual subject in need thereof, comprising administering to the subject a therapeutically effective dose of exogenous NeuroD1 including delivering a recombinant viral expression vector comprising a nucleic acid encoding NeuroD1 to an area wherein normal blood flow has been disrupted n expression vector encoding NeuroD1.
While the claims of the ‘917 Application do not recite the use of a nucleic sequence encoding NeuroD1 polypeptide in combination with a nucleic acid sequence encoding a Dlx2 polypeptide and do not teach hemorrhagic stroke or administering within 3 days of the hemorrhagic stroke, Chen’373, Chen’599, Zhu and Miller teach these limitations for the reasons set forth above. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of generating glutamatergic and GABAergic neurons from astrocytes and converting astrocytes including reactive astrocytes into glutamatergic and GABAergic neurons by expression of exogenous NeuroD1 and exogenous Dlx2 in patients with brain injury or ischemic stroke or hemorrhagic stroke disclosed by Chen’373, Chen’599 and Zhu to the method of the ‘917 Application to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke. It would also have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known technique of administering medication for treatment of stroke including ischemic stroke and hemorrhagic stroke within 3 days disclosed by Miller to the method of the ‘917 Application, Chen’373, Chen’599 and Zhu to generate new glutamatergic and/or GABAergic neurons or increase survival of GABAergic and/or glutamatergic neurons or reducing the number of reactive astrocytes in a mammal having had hemorrhagic stroke to reduce the neuronal damage and neuronal loss caused by hemorrhagic stroke.
This is a provisional nonstatutory double patenting rejection.
Conclusion
12. NO CLAIM IS ALLOWED.
13. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wang et al. (US10076574; published as US20160263233 or WO2015/061779, published Apr 30, 2015, priority Oct 25, 2013) teach a method of treating different diseases including neurological diseases or neuronal tissue damage including ischemic and hemorrhagic stroke using a composition comprising protein transduction reagent-modified reprogramming protein including protein transduction reagent-modified NeuroD1 and protein transduction reagent-modified Dlx2 (col.3, line9; lines 22-23; col. 11, lines 57 and 62; col. 26, lines 16-38; col.28, lines 36-43).
Guo et al. (Cell Stem Cell, 2014; 14:188-202) teach that reactive glial cells (e.g. astrocytes, NG2 cells and microglia) in the cortex of stab-injured or Alzheimer’s disease (AD) model mice can be directly reprogrammed into functional neurons in vivo using retroviral expression of a single neural transcription factor NeuroD1 in the form of a pbCAG-NeuroD1-IRES-GFP or GFAP::NeuroD1-IRES-GFP or NG2::NeuroD1-IRES-GFP by injecting the recombinant retroviral vector into mouse cortex (see at least the Summary). Guo teaches that following expression of NeuroD1, astrocytes were reprogrammed into glutamatergic neurons, while NG2 cells were reprogrammed into glutamatergic and GABAergic neurons (see sections titled “In vivo reprogramming of reactive glial cells into functional neurons after brain injury’; “NeuroD1 reprograms NG2 cells into glutamatergic and GABAergic neurons” and “Reactive glia-neuron conversion in an AD mouse model’). Guo also teaches that NeuroD1 was also capable of reprogramming cultured human astrocytes into functional neurons efficiently (section titled “Reprogramming cultured human astrocytes into functional neurons”). Guo also teaches that “in vivo regeneration of functional neurons from reactive glial cells may provide a potential therapeutic approach to restore lost neuronal function in injured or diseased brain” (p.188, right col., last sentence of second full paragraph); and “NeuroD1 has been reported to be essential for adult neurogenesis.....Other transcription factors such as neurogenin-2 and DIx2 have been shown to reprogram cultured mouse astrocytes into neurons (Heinrich et al., 2010)” (see p. 197, 1st col., last 3 sentences of first full paragraph).
Heinrich et al. (Methods in Molecular Biology, 2012; 814:485-498) teach a protocol that allows for the direct and efficient in vitro reprogramming of mouse astroglia from the early postnatal neocortex by forced expression of single neurogenic fate determinants via retrovirus-mediated expression of neurogenin-2 or Distal-less DIx2 (pCAG-DIx2-IRES-DsRed) or Mash1 (Abstract; page 494, fifth paragraph; and Fig. 3). Heinrich teaches that astroglia transduced with DIx2 develop into GABAergic neurons (p. 497, 1st paragraph). Heinrich teaches that in the case of the brain damage, direct reprogramming of endogenous glia residing in the damaqed tissue, may allow for the replacement of deqenerated neurons without the need of transplantation and its associated complications’ (page 485, first two sentences of first paragraph”; and “Importantly, although the protocol detailed below has been originally developed for early postnatal astroglia, it can also be applied to adult astroglia following injury-induced reactivation and in vitro expansion under neurosphere conditions (10). Single factor reprogramming of astroglia into neurons in vitro provides an experimental model system for attempts aimed at endogenous repair of damaged brain tissue in vivo.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Chang-Yu Wang
September 3, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
Prosecution Insights