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 .
Claim Status
Claims 2, 14-15, 20-22 are cancelled.
Claims 1, 3-13, and 16-19 are amended.
Claims 23-26 are new.
Claims 1, 3-13, 16-19 and 23-26 are examined on the merits.
Priority
The applicant’s application is a U.S. National Stage application of PCT International Patent Application Serial No. PCT/KR2022/001594, filed January 28, 2022, which itself claims the benefit of Korean Patent Application Serial No. KR10-2021-0012117, filed January 28, 2021 is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The substitute specification filed 2/07/2024 has been entered.
The disclosure is objected to because of the following informalities:
Fig. 8, indicates the colors red and green which cannot be seen in the black and white drawings (e.g., paragraph 107).
The terms “Alexa fluor” and Triton” which are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: The word “of” is missing between “consisting” and “V18P” in line 6.
Claim 4 is objected to because of the following informalities: Only a single sequence is selected, “NOs” should be replaced by “NO”.
Claim 5 is objected to because of the following informalities: Only a single sequence is selected, “NOs” should be replaced by “NO”.
Claim 9 is objected to because of the following informalities: the word “a” should be added between “and” and “Kozak” in the last line of the claim to improve the grammar.
Claim 23 is objected to because of the following informalities: Only a single sequence is selected, “NOs” should be replaced by “NO”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 is indefinite because it is not clear if “represented” by SEQ ID: 17, 18, 23, means the promoter must be the sequences of SEQ ID NO: 17, 18, 23, or whether it need only have some similarity to (representation of) SEQ ID NO: 17, 18, 23.
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, 3, 5-13, 16-19, 24 and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 requires the provision of a genus of Aβ peptide variants “containing at least one mutation selected from the group consisting of V18P, F19D, and A21D based on the Aβ42 peptide sequence of SEQ ID NO: 7. The claims encompass any number of mutations of any type, such as an insertion, deletion or substitution, relative to the sequence of SEQ ID NO: 7, as long as the peptide contains at least one of proline (P) or aspartate (D). Thus, the claim encompasses the provision of a large genus of peptides that must function to treat any neurodegenerative disease.
Claim 3 requires the provision of a genus of Aβ variants containing mutation selected from the group consisting of V18P/A21D, and V18/F19D/A21D based on the Aβ42 peptide sequence of SEQ ID NO: 7. The claim encompass any number of mutations of any type, such as an insertion, deletion or substitution, relative to the sequence of SEQ ID NO: 7. The claim is not limited to the specific double V18P/A21D and triple V18P/F19D/A21D mutants. Instead encompasses a very large genus of Aβ variants that possesses these specific mutations in addition to any number of modifications, such as substitutions at any of the other 39 or 40 residues. Thus, the claim encompasses the provision of a large genus of peptides that must function to treat any neurodegenerative disease.
Claim 5 requires the provision of a genus of Aβ variants “containing at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence variation from sequence of SEQ ID NO: 11 or 12. The claim encompass at least 2 mutations of any type, such as an insertion, deletion or substitution, relative to the sequence of SEQ ID NO: 11 or 12; peptides with the specified mutation V18P/A21D (SEQ ID NO 11) or V18P/F19D/A21D (SEQ ID NO 12), plus additional substitutions at the other 40 or 39 positions of the Aβ peptide. Thus, the claim encompasses the provision of a large genus of peptides that must function to treat any neurodegenerative disease.
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 a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
The specification envisions a genetic construct, a recombinant expression vector, and a use thereof, capable of expressing an Aβ variant that slows down or hinders wt Aβ polymerization and reduces its toxicity in the human body (e.g., paragraph 14). The specification envisions a broader genus: The variants according to the present invention may further comprise additional variants thereof to the extent that "biological active" is equally maintained (e.g., paragraph 30). The specification envisions that invention may comprise additional mutations in the sequence of any one of SEQ ID NOs: 9 or 10. Specifically, a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to each sequence may be employed. These sequences are intended to include within the scope of the present invention sequences in which the biological activity of the above Aβ42 peptide variant produced by the encoding sequence is maintained at an equivalent level (e.g., paragraph 31). The specification envisions
that the Aβ42 peptide variant may be any one or more selected from the group consisting of the following sequences, but is not limited thereto: Aβ (V18P/A21D) DAEFRHDSGYEVHHQKLPFFDEDVGSNKGAIIGLMVGGWIA (SEQ ID NO: 11)
Aβ (V18P/F19D/A21D) DAEFRHDSGYEVHHQKLPDFDEDVGSNKGAIIGLMVGGWIA (SEQ ID NO: 12) (e.g., paragraphs [33-35]). The specification envisions the present invention includes all of each mutation of V18P, F19D, or A21D, two combined mutations, and three combined mutations thereof. If desired, sequences having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to SEQ ID NOs: 11 or 12 while including the above-described mutations, may also be included in the scope of the present invention (e.g., paragraph 36).
Although the working examples disclose that the AAV vectors (pAAV-CMV enhancer hSyn- GLSP-Aβ (V18P/F19D/A21D)-KK-WPRE-polyA) and the control AAV (pAAV-CMV enhancer-hSyn-WPRE-polyA) were respectively injected into the brain or vein of 3xTg AD mice, and AD-related markers were observed. In 9 months or 12 months after virus injection, 3xTg AD mice were subjected to behavioral tests and were sacrificed at the end of the tests, and their brains were processed for further biochemical and immunohistochemical analysis (e.g., paragraph 151); the working examples only discloses biochemical, immunohistochemical and behavioral data of the genetic construct pAAV-hSyn-GLSP-Aβ (V18P/F19D/A21D) -KK-WPRE polyA; indicating improving plaque burden by reducing about 78% of Aβ40 and about 64% of Aβ42; and as compared to 3xTg with reduced cognitive function, the mice transfected with the peptide according to the present invention by the AAV virus carrier (pAAV-hSyn-GLSP-Aβ (V18P/F19D/A21D) -KK-WPRE polyA), showed improvement in cognitive function, (e.g., paragraphs [151-171]).
The examples described in the specification does not meet the limitation of the rejected claim containing at least one mutation selected from the group consisting of V18P, F19D, and A21D based on the Aβ42 peptide sequence of SEQ ID NO: 7. Containing “at least one mutation” allows for a very large number of additional mutations (insertions, deletion and substitutions), peptides with the specified mutation (V18P, F19D, and A21D) plus any number of additional substitutions at the other 39 positions of the Aβ peptide. The specification only provides data for three specific species: V18P, F19D and A21D. These 3 species are not representative of the very large variations allowed by the claim, there is insufficient guidance provided indicating any of the elements that are critical to the functioning of the Aβ variant, thus it cannot be determined which amino acid can be changed without disrupting the function of the Aβ variant; thus, further experimentation would be required to determine which variants of e.g., SEQ ID NO: 7 are functional and which are not.
The state of the art with respect to using Aβ variants for treatment of neurodegenerative disease is under developed and unpredictable. Park et al. (Molecular Therapy, 2021) evaluated 5 different Aβ42 variant peptides: V18P, F19D, F19P, F19D/L34P, and F20P for their capacity to prevent aggregation of the wild-type Aβ42 peptide, four of the five variant peptides reduced fibrillization of WT Aβ, whereas one (V18P) exacerbated aggregation; two peptide variants selected for further study, F20P and F19D/L34P, appeared to completely prevent aggregation; both variants disaggregated WT fibrils in a concentration-dependent manner; however, F19D/L34P was considerably more effective at fibril disassembly than F20P, attaining >80% loss of the ThT signal at the highest concentration tested (e.g., paragraph 1st, right column, page 2295; Fig. 1). On the contrary, Park et al. teaches that although both F20P and F19D/L34P significantly diminished the total accumulation of Aβ, F20P was clearly more effective at inhibiting aggregation in APP/ PS1 mice Aβ peptides might be used to alleviate Aβ pathology in a mouse model of Alzheimer’s amyloidosis (e.g., paragraph 1st, left column, page 2299; Fig.4). V18P, as well as F19D/L34P may not work for the “method of treating”. By adding a second mutation to F19D such as L34P (substituted by aspartate and proline residue) diminish the capacity to inhibit the accumulation of total Aβ in the APP/Ps1 animal model.
As such, the prior art teaches about the unpredictability of the treatment of neurodegenerative diseases by administration of a genetic construct carrying an Aβ.
The claims encompasses significantly more than what is disclosed in the specification and does not satisfy the written description requirement under 35 U.S.C 112(a).
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 3, 5-13, 16-19.
The claims listed in the statement of rejection but not otherwise discussed are rejected because they are similarly not limited to particular amino acids that are considered to be adequately described by the specification.
Claims 1, 3-13, 16-19 and 23-26 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 treating Alzheimer’s disease, comprising administering to the subject a therapeutically effective amount of an adeno-associated vector (AAV) comprising a nucleic acid sequence encoding an Aβ peptide variant and a promoter operably linked, and wherein the Aβ variant sequence is SEQ ID NO 9 or 10, and wherein the administration is via intracerebral injection, does not reasonably provide enablement for treating any other neurodegenerative disease, administering any other genetic construct via any other route of administration, or administering any other Aβ peptide variant. Note that the prior art iAβ5 (LPFFD) is enabled but does not find support in the instant application. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404: Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant claim 1 is drawn to a method for treating neurodegenerative diseases comprising administering to the subject a therapeutically effective amount of a genetic construct, wherein the genetic construct comprises a coding sequence encoding an Aβ peptide variant, and wherein the coding sequence encoding the Aβs peptide variant is a sequence encoding a peptide sequence containing at least one mutation selected from the group consisting V18P, F19D, and A21D. The nature of the claims is complicated, because the claim requires the outcome of treating neurodegenerative diseases, yet the claim is drawn to administering a genetic construct encoding an Aβ variant peptide.
Breadth of the claim: The claims encompass a method for treating neurodegenerative diseases comprising administering to the subject a therapeutically effective amount of a genetic construct, wherein the genetic construct comprising: comprises a coding sequence encoding an Aβ peptide variant and a promoter operably linked thereto, and wherein the coding sequence encoding the Aβs peptide variant is a sequence encoding a peptide sequence containing at least one mutation selected from the group consisting V18P, F19D, and A21D based on the Aβ42 peptide sequence of SEQ ID NO: 7. The claims are broad with respect to the treatment of any neurodegenerative disease including, but not limited to, the diseases recited in dependent claim 16. The claims broadly encompass the administration of any sequence encoding any Aβ peptide variant that can differ in any number of mutations relative to SEQ ID NO: 7 so long as it has a proline or aspartate residue. The claims are broad with regard to the genetic construct administered, the claim encompass any type of genetic construct from the group consisting of an adenovirus vector, an adeno-associated virus (AAV) vector, a herpes virus vector, an avipoxvirus vector, and a lentivirus vector. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification envisions a genetic construct, a recombinant expression vector, and a use thereof, capable of expressing an Aβ variant that slows down or hinders wt Aβ polymerization and reduces its toxicity in the human body (e.g., paragraph 14). The specification envisions a broader genus: The variants according to the present invention may further comprise additional variants thereof to the extent that "biological active" is equally maintained (e.g., paragraph 30). The specification envisions that invention may comprise additional mutations in the sequence of any one of SEQ ID NOs: 9 or 10. Specifically, a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to each sequence may be employed. These sequences are intended to include within the scope of the present invention sequences in which the biological activity of the above Aβ42 peptide variant produced by the encoding sequence is maintained at an equivalent level (e.g., paragraph 31). The specification envisions that the Aβ42 peptide variant may be any one or more selected from the group consisting of the following sequences, but is not limited thereto: Aβ (V18P/A21D) DAEFRHDSGYEVHHQKLPFFDEDVGSNKGAIIGLMVGGWIA (SEQ ID NO: 11)
Aβ (V18P/F19D/A21D) DAEFRHDSGYEVHHQKLPDFDEDVGSNKGAIIGLMVGGWIA (SEQ ID NO: 12) (e.g., paragraphs [33-35]). The specification envisions the present invention includes all of each mutation of V18P, F19D, or A21D, two combined mutations, and three combined mutations thereof. If desired, sequences having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to SEQ ID NOs: 11 or 12 while including the above-described mutations, may also be included in the scope of the present invention (e.g., paragraph 36). The specification envisions viral vector including, but are not limited to, an adenovirus vector, an adeno-associated virus (AAV) vector, a herpes virus vector, an avipoxvirus vector (e.g., paragraph 57). The rAAV particles comprise a capsid protein from an AAV capsid serotype selected from AAVl, AAV2, AAV3, AAV4, AAVS, AAV6, AAV7, AAV8, AAV9, AAVl0, AAVll, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rhlO, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSCl, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSCS, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSClO, AAV.HSCll, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, and AAV.HSC1 (e.g., paragraph 59).
The working example, does teach treatment of Alzheimer’s disease a neurodegenerative disease, the working examples disclose that the AAV vectors (pAAV-CMV enhancer hSyn- GLSP-Aβ (V18P/F19D/A21D)-KK-WPRE-polyA) and the control AAV (pAAV-CMV enhancer-hSyn-WPRE-polyA) were respectively injected into the brain or vein of 3xTg AD mice, and AD-related markers were observed. In 9 months or 12 months after virus injection, 3xTg AD mice were subjected to behavioral tests and were sacrificed at the end of the tests, and their brains were processed for further biochemical and immunohistochemical analysis (e.g., paragraph 151). The working examples only discloses biochemical, immunohistochemical and behavioral data of the genetic construct pAAV-hSyn-GLSP-Aβ (V18P/F19D/A21D) -KK-WPRE poly A. The working examples disclose improving plaque burden by reducing about 78% of Aβ40 and about 64% of Aβ42 (e.g., paragraphs [151-171]; Fig. 9). In addition, 3xTg mice which are Alzheimer's dementia model mice and have poor cognitive function and spatial perception that were transfected with the Aβ peptide variant AAV virus carrier (pAAV-hSyn-GLSP-Aβ (V18P/F19D/A21D) -KK-WPRE polyA) showed improvement in cognitive function than that of AAV-hSyn (Control). (e.g., paragraphs [171-172; Fig. 12).
Predictability and state of the art: The state of the art with respect to using Aβ variants for treatment of neurodegenerative disease is under developed and unpredictable. Ichimata et al. (Brain Pathology, 2024) teaches that combinations of one or more proteinopathies (mixed pathology) frequently occur in individuals with neurodegenerative diseases (NDDs), with the major proteins being amyloid-beta (Aβ), tau, α-synuclein, and TAR DNA-binding protein 43 (TDP-43) (e.g., paragraph 1st, page 1). Consequently, it is crucial to comprehend the molecular characteristics of pathological proteins deposited in each non-AD NDD to enhance therapeutic efficacy. However, there is a lack of knowledge regarding the spectrum of Aβ deposition and its association with some factors such as sex and APOE genotype, particularly in non-AD NDDs (e.g., paragraph 4th, left column, page 2). Ichimata discloses a study with 116 autopsies of patients with various non-AD neurodegenerative disorders. Ichimata discloses that the type of concomitant proteinopathies influences the spectrum of AB deposition, impacted also by sex and APOE genotypes (e.g., abstract, Table 1). Hansson et al. (Nat. Medicine 2021) teaches that biomarkers for neurodegenerative diseases are needed to improve the diagnostic workup in the clinic but also to facilitate the development and monitoring of effective disease-modifying therapies (e.g., abstract). Hansson et al. teaches that all neurodegenerative diseases exhibit at least some heterogeneity, such as variations in the localization of disease pathology, the level and type of neuroinflammation or the intensity of neurodegeneration. Certain subgroups, potentially defined by biomarkers, might consequently respond better to certain therapies. Even more likely is that different disease-modifying therapies have different optimal time windows during the disease when they are most effective. When targeting upstream pathologies, such as Aβ in AD and α-synuclein in PD, therapies will likely be more effective during early pre-symptomatic or prodromal disease stages before manifest and irreversible neurodegeneration has occurred (e.g., paragraph 2nd, right column, page 955). Moraca et al. (RSC Med. Chem. 2024) teaches that among the proposed β-sheet breakers, peptide-based inhibitors called β-sheet breaker peptides (BSBPs), represent a major part of the efforts. BSBPs were initially designed by mimicking the hydrophobic core of the amyloidogenic sequence Aβ17–23 LVFFAED, involved in the aggregation process (e.g., paragraph 1st column left, page 2287). A pentapeptide was designed and synthesized by replacing V18P and A21D to achieve the peptide Aβ17–21 LPFFD (also known as iAβ5), which was able to inhibit and disassemble amyloid fibrils in vitro. To minimize exopeptidase cleavage, N-terminal and C-terminal protections were added, leading to the peptide Ac-LPFFD-NH2 (iAβ5p, 1), demonstrating that N-terminal acetylation and C-terminal amidation enhanced stability in both human plasma and cerebrospinal fluid (CSF) (e.g., paragraph 2nd, left column page 2288). Two modified peptides 2 and 3 were identified as the two most promising BSBPs with a significant improvement of the fibrillogenesis inhibition with respect to the reference peptide iAβ5p (e.g., paragraph 2nd, right column, page 2288). Park et al. (Molecular Therapy, 2021) evaluated 5 different Aβ42 variant peptides: V18P, F19D, F19P, F19D/L34P, and F20P for their capacity to prevent aggregation of the wild-type Aβ42 peptide, four of the five variant peptides reduced fibrillization of WT Aβ, whereas one (V18P) exacerbated aggregation; two peptide variants selected for further study, F20P and F19D/L34P, appeared to completely prevent aggregation; both variants disaggregated WT fibrils in a concentration-dependent manner; however, F19D/L34P was considerably more effective at fibril disassembly than F20P, attaining >80% loss of the ThT signal at the highest concentration tested (e.g., paragraph 1st, right column, page 2295; Fig. 1). On the contrary, Park et al. teaches that although both F20P and F19D/L34P significantly diminished the total accumulation of Aβ, F20P was clearly more effective at inhibiting aggregation in APP/ PS1 mice Ab peptides might be used to alleviate Aβ pathology in a mouse model of Alzheimer’s amyloidosis (e.g., paragraph 1st, left column, page 2299; Fig.4).
Thus, the teachings of the post-filing art are consistent with the prior art demonstrating the underdeveloped and unpredictable nature of the invention.
Amount of experimentation necessary: Neurodegenerative diseases are highly complex and different etiologies and gene-based therapies are still in developmental stages. It would require a large amount of experimentation to make use of Aβ variants for treatment of neurodegenerative diseases. For a specific gene therapy to be efficacious, it would require to address: (1) the specific means of Aβ for treatment of neurodegenerative diseases delivery, expression, activity, (2) to define the specific dosage of therapeutic molecules delivered to the cells or to the subjects in time course, (3) the potential deleterious effect of continuous expression of the Aβ on normal cells and tissues.
In view as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1, 3-13, 16-19 and 23-26 are not considered to be fully enabled by the instant disclosure.
In view of the breadth of the claims, the lack of guidance provided by the specification, the lack of the predictability of the art to which the invention pertains, undue amount of experimentation would be required to make and use the claimed invention to treat neurodegenerative diseases in a subject, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on administration of pharmaceutical composition comprising the claimed nucleic acid encoding the Aβ variant protein, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of treating neurodegenerative disease in subject’s brain, the claim is not enabled commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 6-7, 9-13, 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fol et al. (“Fol”, WO 2016/198627 A1) in view of Soto et al. (“Soto”, Nat. Medicine, 1998, cited as reference 2 on IDS filed 02/04/2025).
Regarding claim 1, 16-17, Fol teaches methods and pharmaceutical compositions for the treatment of Alzheimer's disease. In particular the present invention relates to a method of treating Alzheimer's disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a vector which comprises a nucleic acid molecule encoding for a polypeptide which is a soluble member of the APP (amyloid precursor protein) family (e.g., abstract). Fol teaches that overexpression of APPsα by AAV-mediated gene transfer into the brain to explore its potential to ameliorate or rescue structural, electrophysiological and behavioral deficits of AD model mice. Overexpression of APPsα in aged transgenic APP/PS1ΔE9 mice with well-established plaque pathology improves synaptic plasticity and partially rescues spine density deficits. Restoration of synaptic plasticity and increased spine density is also accompanied by a rescue of spatial memory. Moreover, APPsα expression leads to moderately reduced Aβ levels and significantly ameliorated plaque pathology (e.g., lane 26, page 2). Fol teaches the therapeutic potential of APPsα by using AAV-mediated overexpression of APPsα in the brain of aged (12 month-old) APP/PSIΔE9 mice. APP/PSIΔE9 mice show progressive plaque deposition starting at about 5-6 months of age and highly abundant plaques are observed at 12 months of age. AAV9 vectors expressing either Venus or codon optimized HA-tagged murine APPsα (HA-APPsα) under the control of the neuronal synapsin promoter (further referred to as AAV-Venus and
AAV-APPsα, data not shown) were bilaterally injected into the stratum lacunosum moleculare region of the dorsal hippocampus and into the dentate gyrus (data not shown) of 12 month-old male APP/PSΔE9 mice. (e.g., lane7, page 19).
Regarding claims 6-7, Fol teaches examples of promoter include, but are not limited to, the phophoglycerate kinase (PKG) promoter, CAG (composite of the CMV enhancer the chicken beta actin promoter (CBA) and the rabbit beta globin intron.), NSE (neuronal specific enolase), synapsin or NeuN promoters, the SV 40 early promoter, mouse mammary tumor virus L TR promoter; adenovirus major late promoter (Ad MLP); a herpes simplex virus (HSV) promoter, a cytomegalovirus (CMV) promoter such as the CMV immediate early promoter region (CMVIE), SFFV promoter, rous sarcoma virus (RSV) promoter, synthetic promoters, hybrid promoters (e.g., lane 18, page 14).
Regarding claim 9, Fol teaches expression cassette may comprise additional elements, for example, an intron, an enhancer, a polyadenylation site, a woodchuck response element (WRE), and/or other elements known to affect expression levels of the encoding sequence (e.g., lane 34, page 13).
Regarding claims 10-13, Fol teaches viral vectors carrying transgenes are assembled from polynucleotides encoding the transgene, suitable regulatory elements and elements necessary for production of viral proteins which mediate cell transduction. Examples of viral vector include but are not limited to adenoviral, retroviral, lentiviral, herpesvirus and adeno-associated virus (AAV) vectors (e.g., lane 13, page 10). Fol teaches that "AAV vector" is meant a vector derived from an adeno-associated virus serotype, including without limitation AAV1, AAV2, AAV3, AAV4, AAS, AA V6, AAV7, AAV8, AAV9, AAVrhlO or any other serotypes of AAV that can infect humans, monkeys or other species (e.g., lane 20, page 10).
Regarding claim 18, Fol teaches APPsα has its general meaning in the art and refers to the protein formed by the cleavage of the amyloid precursor protein (APP) by the a-secretase. The APPsa is then secreted into the extracellular space (e.g., lane 20, page 5).
Fol does not teach the encoded protein Aβ42 comprising V18P and A21D mutations, as required by the instant claims. However, this is cured by Soto.
Regarding claims 1, 3, Soto teaches that inhibition of cerebral amyloid β-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as β-sheet breakers (e.g., abstract). Soto teaches that a central event in Alzheimer's disease (AD) is the cerebral deposition of amyloid, an insoluble substance composed mainly of the 39-43-residue amyloid beta-protein (AP) (e.g., paragraph 2nd, left column, page 822). Soto teaches the central hydrophobic region in the N-terminal domain of AP, amino acids 17-20 (LVFF) (highlighted in bold and italic are amino acids V, F and A at positions 18, 19 and 21 in WT Aβ42, [see below]), served as a template for designing the P-sheet breaker peptide iAβ5 (LPFFD) (it reads on V18P and A21D substitutions on WT Aβ42 peptide). Amino-acid substitutions in this region of AP produce large changes in the peptide's conformation and its ability to make amyloid fibrils.
WT Aβ42: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
Soto teaches that iAβ5 inhibited, in a dose-dependent manner, amyloid formation by Aβ1-40 and Aβ1-42 in vitro (e.g., paragraph 2nd, page 822; Fig. 1A).
Fig. 1A:
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Regarding claim 19, Soto teaches that a compound (iAβ5) (LPFFD) prevents amyloid neurotoxicity in cell culture, reduces in vivo cerebral Aβ deposition and completely blocks amyloid fibril formation in rat brain (e.g., e.g., paragraph 2nd, left column, page 823; Figs. 4-5).
Fig. 5: Quantitative analysis of the size of Aβ deposits produced after intracerebral injection of Aβ1-42
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Soto teaches that β-sheet breaker peptides or their non-peptidic derivatives have the potential to be therapeutic agents to prevent or retard the progression of amyloidosis in Alzheimer’s disease (e.g., paragraph 1st, right column, page 824).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the teachings of Fol -methods and pharmaceutical compositions for the treatment of Alzheimer's disease, comprising administering to the subject a therapeutically effective amount of an adeno-associated virus (AAV) vector which comprises a nucleic acid molecule encoding for a polypeptide which is a soluble member of the APP (APPsα) under the control of SYN promoter, and substitute the coding sequence of APPsα peptide with the sequence encoding the peptide of Soto comprising V18 and A21D mutations; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing method for treating Alzheimer’s disease with an expression AAV vector comprising a SYN promoter with a gene encoding V18P, or A21D mutations for expression in a neuronal cell to reduce in vivo cerebral Aβ deposition and block amyloid fibril formation in brain.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to try to develop a therapeutic approach to reduce amyloidosis in Alzheimer's disease using an expression vector encoding Aβ variant that can reduce in vivo cerebral Aβ deposition and block amyloid fibril formation in brain.
Claims 4-5, 23 are rejected under 35 U.S.C. 103 as being unpatentable over Fol et al. (“Fol”, WO 2016/198627 A1), and Soto et al. (“Soto”, Nat. Medicine, 1998, cited as reference 2 on IDS filed 02/04/2025) as applied to claims 1, 3, 6-7, 9-13, 16-19 above, and further in view of Villar-Pique et al. (“Villar-Pique”, Biotechnol. J. 2016) .
Fol and Soto do not teach the encoded protein Aβ42 comprising F19D mutation, as required by the instant claims. However, this is cured by Villar-Pique.
Regarding claim 4-5, Villar-Pique teaches that amyloid polymerization underlies an increasing number of human diseases. Villar-Pique exploit the amyloid properties of the inclusions bodies (IBs) formed by amyloidogenic proteins in bacteria to address the kinetics of in vivo amyloid aggregation. Using time-lapse confocal microscopy and a fusion of the amyloid-beta peptide (Aβ42) with a fluorescent reporter (e.g., abstract). Villar-Pique teaches the expression patterns of Aβ42WT-GFP and Aβ42F19D-GFP by inducing the expression of the two proteins in bacteria, evaluating the expression patterns along time and total protein concentration in the cell, to discard that differences in these parameters could influence further characterization of the kinetics of intracellular aggregation in the two polypeptides (e.g., paragraph 1st, right column). Villar-Pique teaches that Aβ42WT-GFP accumulates mainly in the insoluble fraction, whereas Aβ42F19D-GFP is distributed between the soluble (40%) and insoluble (60%) fractions (e.g., paragraph 2nd, right column, page 174, Fig. 1). Villar-Pique teaches that the higher fluorescence of Aβ42F19D-GFP IBs at the end of the experiment already suggested a lower aggregation rate relative to the WT variant (e.g., paragraph 1st, column left, page 175; Table 1).
Fig. 1:
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Villar-Pique teaches that the aggregation of the WT variant is faster than that of the F19D one (e.g., paragraph 2nd, left column, page 175; Fig. 2).
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Villar-Pique teaches all kinetic parameters indicate that the amyloid aggregation of Aβ42F19D-GFP is delayed inside the cell as a consequence of the lower amyloid propensity of Aβ42F19D peptide, confirming a correlation between in vivo kinetic behavior and the predicted amyloid
propensity of the Aβ42 peptide. Indeed, the F19D point mutation not only reduces the overall aggregation propensity of the entire fusion protein, but also alters the polymerization kinetics suggesting that the two proteins might self-assemble inside the cell following different pathways, whose intermediates might impact differently on the cell physiology (e.g., paragraph 1st, right column, page 175; Table 1)
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Fol and Soto -method for treating Alzheimer’s disease with an expression AAV vector comprising a SYN promoter and a gene encoding Aβ variant comprising V18P, or A21D mutations and the teachings of Villar-Pique -the vector expressing Aβ42F19D has lower aggregation and more solubility than WT Aβ42 peptide; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of design Aβ variant amino acid and DNA sequence comprising the V18P and A21D as taught by Soto: SEQ ID NO 11 (amino acid), SEQ ID NO 9 (DNA, using known tools for codon translation):
DAEFRHDSGYEVHHQKLPFFDEDVGSNKGAIIGLMVGGVVIA
And the Aβ variant V18P, F19D and A21D taught by Soto and Villar-Pique: SEQ ID NO 12 (amino acid), SEQ ID NO 10 (DNA, using known tools for codon translation):
DAEFRHDSGYEVHHQKLPDFDEDVGSNKGAIIGLMVGGVVIA
and developing method for treating Alzheimer’s disease with an expression AAV vector comprising a SYN promoter with a gene encoding V18P, F19D or A21D mutations for expression in a neuronal cell to reduce in vivo cerebral Aβ deposition and block amyloid fibril formation in brain.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to try to develop a therapeutic approach to reduce amyloidosis in Alzheimer's disease using an expression vector encoding Aβ variants that can reduce in vivo cerebral Aβ deposition and completely blocks amyloid fibril formation in brain.
Claims 8 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Fol et al. (“Fol”, WO 2016/198627 A1), Soto et al. (“Soto”, Nat. Medicine, 1998, cited as reference 2 on IDS filed 02/04/2025) and Villar-Pique et al. (“Villar-Pique”, Biotechnol. J. 2016), as applied to claims 1, 3-7, 9-13, 16-19, 23 above, and further in view of Kaplitt et al. (“Kaplitt, US 2015/0360049 A1).
Fol, Soto, and Villar-Pique do not teach the SEQ ID NO 17, 18 or 23, as required by instant claims 8 and 26. However, this is cured by Kaplitt.
Regarding claims 8, 26 Kaplitt teaches system for controllably managing motor function in the central nervous system of a patient having a targeted tissue structure that has been genetically modified to have light sensitive protein, comprising a light delivery element configured to direct radiation to at least a portion of a targeted tissue structure (e.g., paragraph 0009). Kaplitt teaches that he promoter within the cassette may confer specificity to a targeted tissue, such as in the case of the human synapsin promoter ("hSyn") or the human Thy1 promoter ("hThyl"), which allow protein expression of the gene under its control in neurons. Kaplitt teaches calmodulin-dependent protein kinase II promoters (e.g. CaMKii, CaMK2A, CaMK2B, CaMK2D, and/or CaMK2G), which allow for targeting of excitatory glutamatergic neurons (e.g., paragraph 0041). Kaplitt teaches SEQ ID NO 60 which has 100% homology with SEQ ID NO 18 of the instant claims (e.g., Fig. 48N, page 57).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Fol, Soto and Villar-Pique, -method for treating Alzheimer’s disease with an expression AAV vector comprising a SYN promoter and a gene encoding Aβ variant comprising V18P, F19D and A21D mutations and the teachings of Kaplitt a vector comprising a calmodulin-dependent protein kinase II promoter (CaMKII) of SEQ ID NO 60; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing method for treating a neurological disease like Alzheimer’s disease with an AAV expression vector comprising the promoter CaMKII with a gene encoding the Aβ variants comprising V18P, A21D mutations (SEQ ID NO 9) or V18P, F19D, A21D (SEQ ID NO 10) for expression in a neuronal cell to reduce in vivo cerebral Aβ deposition and block amyloid fibril formation in brain.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to try to develop a therapeutic approach to reduce amyloidosis in Alzheimer's disease using an expression vector encoding Aβ variants that can reduce in vivo cerebral Aβ deposition and blocks amyloid fibril formation in brain.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Fol et al. (“Fol”, WO 2016/198627 A1), and Soto et al. (“Soto”, Nat. Medicine, 1998, cited as reference 2 on IDS filed 02/04/2025), as applied to claims 1, 3, 6-7, 9-13, 16-19 above, and further in view of and De Vlaam et al. (“De Vlaam, WO 2017 /064308 A1) and Emtage et al. (“Emtage”, WO 2019/164979 A1).
Fol, and Soto do not teach a sequence encoding γ secretase, as required by instant claims 24-25. However, this is cured by De Vlaam and Emtage.
Regarding claim 25, De Vlaam teaches that the production of Aβ in the amyloidogenic pathway results from the sequential cleavage of APP by β-secretase and γ-secretase. Initial cleavage by β-secretase at the beginning of the Aβ fragment generates a large soluble amino terminal fragment (APPsβ) and a membrane tethered C-terminal fragment (APP-CTFβ/C99). C99 is further processed by a membrane-associated multi-subunit enzyme complex (y-secretase) generating an amyloid intracellular domain (AICD) and a secreted Aβ peptide of varying lengths depending on the exact position of γ cleavage (e.g., lane 10, page 2; Figs. 3-4). De Vlaam teaches SEQ ID NO 3 that has 100% homology with SEQ ID NO 14 of the instant claim. De Vlaam teaches that mutations on APP close to the amino-terminus of the Aβ fragment have been shown to alter γ-secretase cleavage events either leading to increased or decreased production of Aβ42 (e.g., Fig. 3).
Fig. 3: (indicating γ secretase cleavage site)
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Emtage teaches methods and compositions for regulating selective expression of a protein (e.g., a therapeutic protein, e.g., a chimeric antigen receptor or T-cell receptor) in cells (e.g., immune cells) (e.g., lane 1, page 2). Emtage teaches an extracellular integrin ligand-binding domain that includes an S2 protease cleavage site; a transmembrane domain; an intracellular regulatory domain that includes a gamma-secretase protease cleavage site; and an intracellular transcriptional regulatory domain; wherein, when the chimeric transmembrane receptor is expressed in a mammalian cell, binding of the extracellular antigen-binding domain to the target antigen induces (1) cleavage of the extracellular integrin-ligand binding domain at the S2 protease cleavage site and (2) cleavage of the intracellular regulatory domain at the gamma-secretase protease cleavage site, thereby releasing the intracellular transcriptional regulatory domain from the transmembrane domain (e.g., lane 7, page 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the combined teachings of Fol and Soto to include the sequence encoding a γ secretase cleavage site of De Vlaam, because the production of Aβ in the amyloidogenic pathway results from the sequential cleavage of APP by β-secretase and γ-secretase and the teachings of Emtage -methods and compositions for regulating selective expression of a protein in cells and cleavage of the intracellular regulatory domain at the γ-secretase protease cleavage site, thereby releasing the intracellular transcriptional regulatory domain from the transmembrane domain; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of releasing the Aβ variants to reduce in vivo cerebral Aβ deposition and block amyloid fibril formation in brain.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop a therapeutic approach
to reduce amyloidosis in Alzheimer's disease using an expression vector encoding Aβ variant that can be released to the extracellular milieu that can reduce in vivo cerebral Aβ deposition and completely blocks amyloid fibril formation in brain.
Double Patenting
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-13, 16-19, 23-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8-14, 17-18, 25-29 of copending Application No. 18/274,634.
Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 1 of the ‘634 application is drawn to “A method or treating neurodegenerative diseases comprising administering to the subject a therapeutically effective amount of a genetic construct, wherein the genetic construct comprises: a first coding sequence encoding an Aβ peptide variant; a second coding sequence encoding a tau inhibitor peptide; and a promoter operably linked thereto, and wherein the first coding sequence encoding the Ap peptide variant is a sequence encoding a peptide sequence containing any one or more mutations selected from the group consisting of V18P, F19D, F20P, A21D and L34P based on the Aβ42 peptide sequence of SEQ ID NO: 11.” SEQ ID NO: 11 of the ’634 application is identical to instant SEQ ID NO: 7 (See the alignment below). Claim 1 encompasses embodiments where the one or more mutations are selected from V18P, F19D, and A21D. Those embodiments of the ‘634 application anticipate instant claim 1.
SEQ ID 7 vs SEQ ID 11:
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Claim 3 of the ‘634 application is drawn to “The method of claim 1, wherein the first coding sequence encoding the Aβ peptide variant is a sequence encoding a peptide sequence containing any one mutation selected from the group consisting of F19D/L34P, F20P,V18P/A21D, and V18P/F19D/A21D based on the Aβ42 peptide sequence of SEQ ID NO: 11. Claim 3 encompass embodiments where AB peptide variant is V18P/A21D or V18P/F19D/A21D. Those embodiments of the “634” application anticipate instant claim 3.
Claim 4 of the ‘634 application is drawn to “The method of claim 1, wherein the first coding sequence encoding the Aβ peptide variant is any one selected from the group consisting of SEQ ID NOs: 13 to 16. ” SEQ ID NO: 15 and 16 of the “634” application are identical to instant SEQ ID NO: 9 and SEQ ID NO 10 respectively (See the alignment below). Claim 4 encompasses embodiments where the AB peptide variant sequences are SEQ ID 9 (SEQ ID NO 15) and SEQ ID NO 10 (SEQ ID NO 16). Those embodiments of the ‘634 application anticipate instant claim 4.
SEQ ID 9 vs SEQ ID 15:
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SEQ ID 10 vs SEQ ID 16:
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Claim 5 of the ‘634 application is drawn to “The method of claim 1, wherein the Aβ peptide variant is the sequence having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to any one selected from the group consisting of SEQ ID NOs: 17 to 20”. ” SEQ ID NO: 19 and SEQ ID NO 20 of the ’634 application is identical to instant SEQ ID NO: 11 and SEQ ID NO 12 (See the alignment below). Claim 5 encompasses embodiments where the AB variant sequences are SEQ ID 11 (SEQ ID 19) and SEQ ID NO 12 (SEQ ID NO 20. Those embodiments of the ‘634 application anticipate instant claim 5.
SEQ ID 11 vs SEQ ID 19:
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SEQ ID 12 vs SEQ ID 20:
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Claim 8 of the ‘634 application is drawn to “The method of claim 1, wherein the promoter is any one selected from the group consisting of a human synapsin I (SYN) promoter, a mouse calcium/calmodulin-dependent protein kinase II (CaMKII) promoter, a rat tubulin alpha I (Tal) promoter, a rat neuron-specific enolase (NSE) promoter, a human platelet-derived growth factor- beta chain (PDGF) promoter, an EF-1a promoter, a CAG promoter and a CV promoter. Claim 6 encompasses embodiments wherein the promoter is an overexpression promoter or a neuron-specific promoter. Claim 7 encompasses embodiments where the promoter is selected from human synapsin I (SYN) promoter, a mouse calcium/calmodulin-dependent protein kinase II (CaMKII) promoter, a rat tubulin alpha I (Tal) promoter, a rat neuron-specific enolase (NSE) promoter, a human platelet-derived growth factor- beta chain (PDGF) promoter, an EF-a1 promoter, a CAG promoter and a CMV promoter. Those embodiments of the ‘634 application anticipate instant claims 6 and 7.
Claim 9 of the ‘634 application is drawn to “The method of claim 8, wherein the promoter is a human synapsin I (SYN), CaMKII or CAG promoter, represented by SEQ ID NO: 51, 52 or 57, respectively. ” SEQ ID NO: 51, 52 and 57 of the “634” application are identical to instant SEQ ID NO: 17, 18, and 23, respectively (See the alignment below). Claim 8 encompasses embodiments where the AB variant sequences are SEQ ID 17 (SEQ ID NO 51), SEQ ID NO 18 (SEQ ID NO 52) and SEQ ID NO 23 (SEQ ID NO 57). Those embodiments of the ‘634 application anticipate instant claim 8.
SEQ ID 17 vs SEQ ID 51:
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SEQ ID 23 vs SEQ ID 57:
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Claim 10 of the ‘634 application is drawn to “The method of claim 1, wherein the genetic construct further comprises at least one selected from the group consisting of an enhancer sequence, a polyadenylation sequence, and Kozak sequence. Claim 9 encompasses embodiments where the genetic construct comprises an enhancer sequence, a polyadenylation sequence, and Kozak sequence. Those embodiments of the ‘634 application anticipate instant claim 9.
Claim 11 of the ‘634 application is drawn to “The method of claim 1, wherein the genetic construct is a recombinant expression. Claim 10 encompasses embodiments where the genetic construct is a recombinant expression vector. Those embodiments of the ‘634 application anticipate instant claim 10.
Claim 12 of the ‘634 application is drawn to “The method of claim 11, wherein the recombinant expression vector is any one selected from the group consisting of an adenovirus vector, an adeno-associated virus (AAV) vector, a herpes virus vector, an avipoxvirus vector, and a lentivirus vector. Claim 11 encompasses embodiments wherein the recombinant expression vector is any one selected from the group consisting of an adenovirus vector, an adeno-associated virus (AAV) vector, a herpes virus vector, an avipoxvirus vector, and a lentivirus vector. Those embodiments of the ‘634 application anticipate instant claim 11.
Claim 13 of the ‘634 application is drawn to “The method of claim 12, wherein the recombinant expression vector is the adeno-associated virus (AAV) vector, which is any one selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV 11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, and AAV.HSC16. Claim 12 encompasses embodiments wherein the recombinant expression vector is the adeno-associated virus (AAV) vector, which is any one selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, AAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15 and AAV.HSC16. Those embodiments of the ‘634 application anticipate instant claim 12.
Claim 14 of the ‘634 application is drawn to “The method of claim 13, wherein the adeno-associated virus (AAV) vector is any one selected from the group consisting of AAV2, AAV7, AAV8, AAV9, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4- 1, AAV.hu37, AAV.PHP.B, AAV.PHP.eB, and AAV.7m8. Claim 13 encompasses embodiments wherein the adeno-associated virus (AAV) vector is any one selected from the group consisting of AAV2, AAV7, AAV8, AAV9, AAV.rh8, AAV.rh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4- 1, AAV.hu37, AAV.PHP.B, AAV.PHP.eB, and AAV.7m8. Those embodiments of the ‘634 application anticipate instant claim 13.
Claim 17 of the ‘634 application is drawn to “The method claim 1, wherein the neurodegenerative disease is any one selected from the group consisting of Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia- telangiectasia, neuronal ceroid lipofuscinoses, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal lobe degeneration, Gaucher disease, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Lewy body dementia, lysosomal storage disorder, neuroborreliosis, Machado-Joseph disease, motor neuron disease, multisystem atrophy, multiple sclerosis, multiple sulfatase deficiency, mucolipidosis, narcolepsy, Niemann-Pick type C, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, Pompe disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease, spinocerebellar ataxia, spinal muscular atrophy, Steele Richardson Olszewski syndrome, spinal cord syphilis, and Tay-Sachs disease. Claim 16 encompasses embodiments wherein the neurodegenerative disease is any one selected from the group consisting of Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia- telangiectasia, neuronal ceroid lipofuscinoses, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal lobe degeneration, Gaucher disease, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Lewy body dementia, lysosomal storage disorder, neuroborreliosis, Machado-Joseph disease, motor neuron disease, multisystem atrophy, multiple sclerosis, multiple sulfatase deficiency, mucolipidosis, narcolepsy, Niemann-Pick type C, Niemann-Pick disease, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, Pompe disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease, spinocerebellar ataxia, spinal muscular atrophy, Steele Richardson Olszewski syndrome, spinal cord syphilis, and Tay-Sachs disease. Those embodiments of the ‘634 application anticipate instant claim 16.
Claim 18 of the ‘634 application is drawn to “The method of claim 17 wherein the neurodegenerative disease is Alzheimer's disease. Claim 17 encompasses embodiments wherein the neurodegenerative disease is Alzheimer's disease. Those embodiments of the ‘634 application anticipate instant claim 17.
Claim 28 of the ‘634 application is drawn to “The method of claim 1, wherein the Aβ peptide variant is expressed in the extracellular space. Claim 18 encompasses embodiments wherein the Aβ peptide variant is expressed in the extracellular space. Those embodiments of the ‘634 application anticipate instant claim 18.
Claim 29 of the ‘634 application is drawn to “The method of claim 1, wherein the Aβ peptide variant prevents the extracellular accumulation of aggregated amyloid-β protein. Claim 19 encompasses embodiments wherein the Aβ peptide variant prevents the extracellular accumulation of aggregated amyloid-β protein. Those embodiments of the ‘634 application anticipate instant claim 19.
Claim 5 of the ‘634 application is drawn to “The method of claim 1, wherein the Aβ peptide variant is the sequence having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to any one selected from the group consisting of SEQ ID NOs: 17 to 20”. ” SEQ ID NO: 19 and SEQ ID NO 20 of the ’634 application are identical to instant SEQ ID NO: 11 and SEQ ID NO 12 (See the alignment before). Claim 23 encompasses embodiments where the AB variant sequences are SEQ ID 11 (SEQ ID 19) and SEQ ID NO 12 (SEQ ID NO 20. Those embodiments of the ‘634 application anticipate instant claim 23.
Claim 26 of the ‘634 application is drawn to “The method of claim 1, wherein the genetic construct further comprises a sequence encoding γ secretase cleavage. Claim 24 encompasses embodiments wherein the genetic construct further comprises a sequence encoding γ secretase cleavage. Those embodiments of the ‘634 application anticipate instant claim 24.
Claim 27 of the ‘634 application is drawn to “The method of claim 26, wherein the sequence encoding γ secretase cleavage is SEQ ID NO: 50. ” SEQ ID NO: 50 of the “634” application are identical to instant SEQ ID NO: 14 (See the alignment below). Claim 25 encompasses embodiments where sequence encoding γ secretase cleavage is SEQ ID NO: 14 (SEQ ID NO 50). Those embodiments of the ‘634 application anticipate instant claim 25.
SEQ ID 14 vs SEQ ID 50:
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Claim 4 of the ‘634 application is drawn to “The method of claim 1, wherein the first coding sequence encoding the Aβ peptide variant is any one selected from the group consisting of SEQ ID NOs: 13 to 16. ” SEQ ID NO: 15 and 16 of the “634” application are identical to instant SEQ ID NO: 9 and SEQ ID NO 10 respectively (See the alignment above). Furthermore, Claim 9 of the ‘634 application is drawn to “The method of claim 8, wherein the promoter is a human synapsin I (SYN), CaMKII or CAG promoter, represented by SEQ ID NO: 51, 52 or 57, respectively. ” SEQ ID NO: 51, 52 and 57 of the “634” application are identical to instant SEQ ID NO: 17, 18, and 23, respectively (See the alignment above). Claim 26 encompasses embodiments wherein the coding sequences encoding the Aβ peptide variant is SEQ ID NOs: 9 (SEQ ID 15) or 10 (SEQ ID NO 16), and the promoter is SEQ ID NO: 17 (SEQ ID NO 51), 18 (SEQ ID NO 52) or 23 (SEQ ID NO 57). Those embodiments of the ‘634 application anticipate instant claim 26.
Conclusion
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637