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 .
Priority
Applicant’s claim to priority from International Application PCT/US21/64415 filed 12/20/2021 and from Provisional Application No. 63/127,882 filed 12/18/2020 is hereby acknowledged.
Election/Restrictions
Applicant’s election without traverse of Invention Group I (claims 1-18 drawn to an expression vector) and Species A1 (claims 1 and 2, drawn to an adeno-associated virus (AAV), Species B1 (claims 1, 11-14, drawn to one or more foreign DNA sequences of claim 11), Species C1 (claims 1 and 17, drawn to a tetracycline response element (TRE)) and Species D2 (claims 1 and 18, drawn to an intracellular or extracellular secretion sequences including “YGRKKRRQRRR” sequence) in the reply filed on 06/01/2026 is acknowledged.
NOTE: For Species B (claims 1, 11-14, drawn to one or more foreign DNA sequences of claim 11), Species B1 were elected as a generic subspecies. In the Restriction Requirement dated 04/01/2026, Examiner stated that “Applicant must pick one or more specific foreign DNA sequence”. Applicant did not provide one or several specific gene names or SEQ ID NO(s). Since the election/response is incomplete, Examiner interprets that any one of these subspecies qualifies as part of the invention.
Claims 12-14 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/01/2026.
Application Status
This Office Action is in response to Remarks and amendments filed 06/01/2026.
This Application is a National Stage entry of the International Application PCT/US21/64415 filed 12/20/2021, under 35 U.S.C. § 371.
Amendments to claims filed 06/01/2026 are hereby acknowledged.
Claims 1-19 are currently pending. Claims 12-14 and 19 are withdrawn. Claims 6, 11 and 17-18 are currently amended.
Therefore, claims 1-11 and 15-18 are under consideration in this Office Action.
Any objection or rejection not reiterated herein has been overcome by amendments and is therefore withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/20/2023 is hereby acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The Drawings filed 06/23/2023 are hereby acknowledged and are acceptable.
Specification
The amendments to Specification filed 06/01/2026 are hereby acknowledged. The marked-up copy and substitute clean copy of the Specification filed 06/01/2026 are appreciated and acknowledged.
However, the disclosure is objected to because of the following informalities:
The Specification states: “GH replacement therapy in patients who are suffered from GH deficiency (GHD)…” (see [0005]); and “to elicit therapeutic effect on patients who are suffered from neurodegenerative disorders…” (see [0037]); and “for treatment of those patients who are suffered from neurodegenerative disorders…” ([00140]).
These should read: “…patients who are suffering from …” or “…patients who suffered from…”.
Also, RNAlater® is a trademark owned by AMBION, Inc., not QIAGEN (see [00107]).
The Specification recites “RNA 6000 Nano Market” ([00107]). It should read: “RNA 6000 Nano marker”.
The Specification recites “SortMax Pro Software (Molecular Devices, LLC)” ([00112]); it should read “SoftMax® Pro Software (Molecular Devices, LLC)”.
Appropriate correction is required.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o).
Correction of the following is required: when an abbreviation is used for the first time, it is conventional to write the term in full followed by the abbreviation in parenthesis ( In Figure 1, and in the Description of the Figure in paragraph [0011]), there is no definition for the abbreviations “bla”, “P(A)”,”2A”, “ITR”, “hGH(+GS)” and “AMPR”.
The use of the terms “Cold Fusion” ([0063]), “Applied Biological Materials” or “abm” ([0090]) , “Polybrene” ([0091]), “Penstrep” ([0091]), “lipofectamine” ([0092]), “Benzonase” ([0098]), “Slide-A-Lyzer 10K” ([00100]), “HiTrap” ([00101]), “Amicon ultra-4” ([00102]), “Harvard Apparatus” ([00104]), “Tissue-Tek” ([00105]), “Northern Light” ([00106]), “RNAlater” ([00107]), “QIAzol” ([00107]), “RNeasy” ([00107]), “2100 Bioanalyzer” and “Agilent 2100 bioanalyzer” ([00107]), “SuperScript” ([00108], [00117], [00119]), “Taqman” ([00108], [00109], [00117], [00119]), “Bio-Rad” ([00109]), “Graphpad Prism”, “Excel” ([00112]), “SoftMax” ([00112]), “GeneSpring” ([00112]), “Metacore” ([00112]), “Olympus” and “FluoView” ([00122], [00125], [00127]), “Fluorostar” ([00130]), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites: “an insulator, configured for stable and safety expression”. The claim should read: “an insulator, configured for stable and safe expression”.
Claim 1 also recites “a marker gene, configured to encoding one or more corresponding proteins”. The claim should read: “ a marker gene, configured to encode one or more corresponding proteins”.
Claim 5 is objected to because of the following informality: the claim recites “ a neuronal promoter, including human synapsin, configured to drive expression of transgenes in neurons in a central nervous system (CNS)”. The claim is missing a term, and should read: “ a neuronal promoter, including human synapsin promoter, configured to drive expression of transgenes in neurons in a central nervous system (CNS)”.
Claim 17 is objected to because of the following informality: the claim recites “(2) a post-transcriptional regulatory element (PRE)+ derived from woodchuck hepatitis virus (WHV) into 3’ untranslated region of the AAV vector or lentiviral vector…”. The claim should read: “(2) a post-transcriptional regulatory element (PRE)+ derived from woodchuck hepatitis virus (WHV) inserted into the 3’ untranslated region of the AAV vector or lentiviral vector…” or “(2) a post-transcriptional regulatory element (PRE)+ derived from woodchuck hepatitis virus (WHV) in the 3’ untranslated region of the AAV vector or lentiviral vector…”.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims (claims 1 and 5) in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier.
Such claim limitation(s) is/are: “a promoter, configured to drive expression”, “an insulator, configured for stable and safety expression”, “a marker gene, configured to encoding one or more corresponding proteins”, a regulator element, configured to control expression of the hGH” in claim 1; and “a neuronal promoter, including human synapsin, configured to drive expression of transgenes in neurons” in claim 5.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5, 7-11, 15-16, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims 1 and 5 comprise limitations that invoke 35 U.S.C. 112(f), but the
Specification does not link structure to function.
Whenever the term “configured” is used in the disclosure, it is for repeating the recitation used in the claims without further elaboration on the position/arrangements of sequences and structures’ sequences in relation with the functions recited.
Regarding claims 1 and 5, the Drawings present only one possible arrangement without specifying the sequences of the structures in the arrangement. Paragraph [0011] describes the Figure 1 as an example of multiple gene expression vector, without further addressing the presence/arrangement/structure of the insulator.
Thus, the specification does not disclose adequate structure to perform the claimed functions.
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 1-2, 5, 7-11, 15-16, and 18 are rejected under 35 U.S.C. §112(b) or 35 U.S.C. §112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 5, the term “configured to” invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. Therefore, the claims are indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function.
For more information, see 37 CFR l.75(d) and MPEP §§ 608.0l(o) and 2181.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 7, 8 and 9, they are drawn to an expression vector, and to
further limitation to “a surface capsule of the expression vector”. There is no definition of the terms “a surface capsule” in the Specification. Therefore, the claims are indefinite.,
Regarding claim 10, the claim recites the limitation "a biological tracer" in the
“wherein” clause. There is insufficient antecedent basis for this limitation in the claim. The relationship between a biological tracer (i.e., any biological tracer, a random biological tracer) and the claimed vector is unclear.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10, 15 and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 10, the claim recites a structure, i.e., “a biological tracer” that does not appear in claim 1. The claim further recites intended use of said biological tracer. The use of a product cannot be claimed together with a product itself, as these are two distinct patentable entities. Furthermore, the claim does not add further limitation to the structure claimed in claim 1.
Regarding claims 15 and 16, the claims further recite intended use of the claimed expression vector. The method of use of a product cannot be claimed together with the product itself, as these are two distinct and patentable entities. Furthermore, the claim does not add further limitation to the structure claimed.
Regarding claim 16, the claim further recites steps of a method of use and is also drawn to formulations without specifically and clearly defining the relationship between the formulations and the claimed product.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 10 and 17 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Genkin (Genkin, D.D. et al. WO 2019/143272 A1 published July 25, 2019).
Regarding claim 1, it recites “An expression vector for amplified expression in mammalian cells, comprising:
one or more inserted foreign DNA sequences, including human growth hormone (hGH) and a plurality of therapeutic genes, wherein the one or more inserted foreign DNA sequences are fused with intracellular or extracellular secretion sequences;
a promoter, configured to drive expression of the one or more inserted foreign DNA sequences;
an insulator, configured for stable and safety expression of the one or more inserted foreign DNA sequences;
a marker gene, configured to encoding one or more corresponding proteins to indicate the expression of the one or more inserted foreign DNA sequences; and
a regulator element, configured to control expression of the hGH and the plurality of therapeutic genes under a controllable condition.”
Genkin teaches an expression vector to be used in liver in vivo in mice (i.e., in mammalian cells) (see Figure 6 and {0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a hGH polyA signal, i.e., a foreign DNA sequence including a human Growth Hormone DNA sequence (see [0098], [0291], [0306]).
Genkin also teaches one or more foreign DNA sequences fused to intracellular or extracellular secretion sequences (see [0018], [0082], [0198], claims 69 and 218).
Genkin teaches that the recombinant expression vector comprises a promoter operably linked to a nucleotide sequence encoding an enzyme having deoxyribonuclease (DNase) activity, i.e., one inserted foreign DNA sequence (see [0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a chicken β-globin insulator (see [0225]).
Genkin teaches that the recombinant expression vector comprises an AmpR marker, i.e., as foreign DNA sequences that encodes for one or more corresponding proteins (see [0098], [00102]). Genkin teaches that one foreign DNA sequence can be a marker and/or reporter gene encoding for an antibiotic resistance gene, a fluorescent protein (e.g., GFP) or a gene encoding a chemically, enzymatically or otherwise detectable and/or selectable product (e.g., lacZ, aph, etc.) ([0197], [0222]).
Genkin teaches that the recombinant expression vector further comprises a post-transcriptional regulatory element, a woodchuck hepatitis post-transcriptional regulatory element (WPRE) ( see [0029]). Genkin also teaches that the expression vector can comprise an ApoE enhancer that is a hepatic control region (HCR) enhancer, i.e., to control expression of the foreign DNA sequences, including the foreign hGH polyA sequence, and therapeutic genes under a controllable condition (see [0026]).
Regarding claim 2, Genkin teaches that the expression vector includes an adenoviral associated virus (AAV) vector (see [0024], [0026]-[0038]). Genkin also teaches that in some embodiments, the viral elements can be from a lentivirus such as HIV (see [0221], [0224]-[0225]).
Regarding claim 3, Genkin teaches that the promoter of the expression vector can be a CMV promoter (see [0098], [0135], [0192], [0218], [0225], [0306], Figure 5C, Figure 12). Genkin also teaches in one embodiment an EF-1a promoter (see [00102], Figure 9).
Regarding claim 4, Genkin teaches that the recombinant expression vector comprises an AmpR marker, i.e., as foreign DNA sequences that encodes for one or more corresponding proteins (see [0098], [00102]). Genkin teaches that one foreign DNA sequence can be a marker and/or reporter gene encoding for an antibiotic resistance gene, a fluorescent protein (e.g., GFP) or a gene encoding a chemically, enzymatically or otherwise detectable and/or selectable product (e.g., lacZ, aph, etc.) ([0197], [0222]).
Regarding claim 10, Examiner interprets the claim limitations as one that requires the biological marker/tracer to permit the tracing and detection of the expression vector in isolated cells or in an animal model in vivo. Genkin teaches that an exogenous amino acid sequence, e.g., an exogenous targeting sequence that can be an antibody or an antigen-recognizing moiety, inserted into the virion capsid may be one that facilitates purification or detection of the virion by an art-recognized means such as an antibody-based assays (see [0164], [0203]-[0204]).
Regarding claim 17, Examiner interprets the limitation “a post-transcriptional regulatory element (PRE)+ derived from woodchuck hepatitis virus (WHV)” as a sequence of the woodchuck hepatitis virus that is the post-transcription regulatory element WPRE.
Genkin teaches that the recombinant expression vector further comprises a post-transcriptional regulatory element, a woodchuck hepatitis post-transcriptional regulatory element (WPRE) ( see [0029]). Genkin also teaches in Figure 10A that the WPRE is located in the 3’ end region of the foreign DNA sequence encoding for the therapeutic enzyme (see Figure 10A and [0100]).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 5 is rejected under 35 U.S.C. §103 as being unpatentable over Genkin (Genkin, D.D. et al. WO 2019/143272 A1 published July 25, 2019), as applied to claims 1-4, 10 and 17 above and in further view of Glover (Glover, C.P.J. et al. “Adenoviral-mediated, high-level, cell-specific transgene expression: a SYN1-WPRE cassette mediates increased transgene expression with no loss of neuron specificity”. Molecular Therapy, Vol. 5, No. 5, Part 1/2 (2002), pp: 509-516).
It is noted that Genkin anticipates all the elements of claim 1. Therefore, claim 1 is also rendered obvious by the combination of Genkin and Glover since:
Genkin teaches an expression vector to be used in liver in vivo in mice (i.e., in mammalian cells) (see Figure 6 and {0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a hGH polyA signal, i.e., a foreign DNA sequence including a human Growth Hormone DNA sequence (see [0098], [0291], [0306]).
Genkin also teaches one or more foreign DNA sequences fused to intracellular or extracellular secretion sequences (see [0018], [0082], [0198], claims 69 and 218).
Genkin teaches that the recombinant expression vector comprises a promoter operably linked to a nucleotide sequence encoding an enzyme having deoxyribonuclease (DNase) activity, i.e., one inserted foreign DNA sequence (see [0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a chicken β-globin insulator (see [0225]).
Genkin teaches that the recombinant expression vector comprises an AmpR marker, i.e., as foreign DNA sequences that encodes for one or more corresponding proteins (see [0098], [00102]). Genkin teaches that one foreign DNA sequence can be a marker and/or reporter gene encoding for an antibiotic resistance gene, a fluorescent protein (e.g., GFP) or a gene encoding a chemically, enzymatically or otherwise detectable and/or selectable product (e.g., lacZ, aph, etc.) ([0197], [0222]).
Genkin teaches that the recombinant expression vector further comprises a post-transcriptional regulatory element, a woodchuck hepatitis post-transcriptional regulatory element (WPRE) ( see [0029]). Genkin also teaches that the expression vector can comprise an ApoE enhancer that is a hepatic control region (HCR) enhancer, i.e., to control expression of the foreign DNA sequences, including the foreign hGH polyA sequence, and therapeutic genes under a controllable condition (see [0026]).
Regarding claim 5, Genkin teaches a method to treat neurodegeneration and diseases involving primary or secondary neurodegeneration (see [0137]).
However, Genkin does not teach specifically a neuronal promoter, including a human synapsin promoter, configured to drive expression of transgenes in neurons in a central nervous system (CNS).
Glover teaches an expression vector comprising a synapsin (SYN1) promoter and a woodchuck hepatitis virus post-transcriptional regulatory element WPRE (see title and abstract). Glover teaches an adeno-associated virus as a recombinant vector comprising a foreign DNA sequence used as a marker/reporter (Enhanced Green Fluorescent Protein EGFP), as well as a CMV promoter (see Figure 1) and compared its efficiency and specificity of expression when the CMV promoter is substituted with a SYN1 promoter (see Figure 3).
Glover teaches that the construct expression is specific to neurons (see page 511, left column, “EGFP reporter gene expression following transfection of primary dissociated hippocampal neurons and organotypic hippocampal slices” section).
Glover also teaches that using a cassette combining SYN1 promoter and WPRE sequences in an AAV vector, leads not only to high neuronal specificity (see page 511, left column, second paragraph), but also to effective, strong, long-term transgene expression (see page 514, left column, second paragraph).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the CMV promoter taught in Genkin with a SYN1 promoter taught by Glover. Glover teaches that using the SYN1 promoter leads to a more efficient and specific expression in neurons. One with ordinary skills in the art, motivated into expression a therapeutic agent directly into the brain to target neurodegeneration, could have performed this modification with a reasonable expectation of success and would have arrived to the claimed invention.
Claim 7-8 and 11 are rejected under 35 U.S.C. §103 as being unpatentable over Genkin (Genkin, D.D. et al. WO 2019/143272 A1 published July 25, 2019), as applied to claims 1-4, 10 and 17 above and in further view of Chen (Chen, X. et al. “Different serotypes of Adeno-Associated Virus Vector- and Lentivirus-mediated tropism in Choroid Plexus by intracerebroventricular delivery”. Human Gene Therapy, Vol. 31, No. 7-8 (2020), pp: 440-447), Pardridge (Pardridge, W.M. “Re-engineering therapeutic antibodies for Alzheimer’s disease as blood-brain barrier penetrating bi-specific antibodies”. Expert Opinion on Biological Therapy, Vol. 16, No. 12 (2016), pp: 1455-1468) and Verhelle (Verhelle, A. et al. “AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model”. Human Molecular Genetics, Vol. 26, No.7 (2017), pp: 1353-1364).
It is noted that Genkin anticipates all the elements of claims 1 and 2. Therefore, claims 1 and 2 are also rendered obvious by the combination of Genkin and Glover since:
Regarding claim 1, Genkin teaches an expression vector to be used in liver in vivo in mice (i.e., in mammalian cells) (see Figure 6 and {0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a hGH polyA signal, i.e., a foreign DNA sequence including a human Growth Hormone DNA sequence (see [0098], [0291], [0306]).
Genkin also teaches one or more foreign DNA sequences fused to intracellular or extracellular secretion sequences (see [0018], [0082], [0198], claims 69 and 218).
Genkin teaches that the recombinant expression vector comprises a promoter operably linked to a nucleotide sequence encoding an enzyme having deoxyribonuclease (DNase) activity, i.e., one inserted foreign DNA sequence (see [0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a chicken β-globin insulator (see [0225]).
Genkin teaches that the recombinant expression vector comprises an AmpR marker, i.e., as foreign DNA sequences that encodes for one or more corresponding proteins (see [0098], [00102]). Genkin teaches that one foreign DNA sequence can be a marker and/or reporter gene encoding for an antibiotic resistance gene, a fluorescent protein (e.g., GFP) or a gene encoding a chemically, enzymatically or otherwise detectable and/or selectable product (e.g., lacZ, aph, etc.) ([0197], [0222]).
Genkin teaches that the recombinant expression vector further comprises a post-transcriptional regulatory element, a woodchuck hepatitis post-transcriptional regulatory element (WPRE) ( see [0029]). Genkin also teaches that the expression vector can comprise an ApoE enhancer that is a hepatic control region (HCR) enhancer, i.e., to control expression of the foreign DNA sequences, including the foreign hGH polyA sequence, and therapeutic genes under a controllable condition (see [0026]).
Regarding claim 2, Genkin teaches that the expression vector includes an adenoviral associated virus (AAV) vector (see [0024], [0026]-[0038]). Genkin also teaches that in some embodiments, the viral elements can be from a lentivirus such as HIV (see [0221], [0224]-[0225]).
Regarding claims 7-8 and 11, Examiner interprets the claim 7’s limitations as requiring a targeting moiety expressed at the viral capsid’s surface, said targeting moiety being encoded by a nucleic acid sequence that is comprised within a viral expression vector, and said targeting moiety permits the targeting and attachment on specific isolated cells or on specific tissues, i.e., choroid plexus and blood brain barrier (BBB) tissues, in an animal model in vivo. Examiner interprets that said targeting moiety is required in claim 8 to be a single-chain fragment variable (scFv) antibody that binds to one or more recognition sites on choroid plexus and blood brain barrier (BBB) tissues.
Genkin teaches that an exogenous amino acid sequence, e.g., an exogenous targeting sequence that can be an antibody or an antigen-recognizing moiety, inserted into the virion capsid may be one that facilitates purification or detection of the virion by an antibody-based assay (see [0164],[0203]-[0204]). Genkin also teaches exogenous targeting moieties that can be an antibody, or a fragment thereof ( see [0204]-[0205]).
Genkin also teaches using AAV2, AAV5, AAV8 and AAV9 are alternative serotypes for the AAV vector (see [0184]).
As evidenced by Chen, the Choroid Plexus is preferably targeted by AAV2/5 and AAV2/8 serotypes (see title and abstract). Therefore, Genkin teaches the use of serotypes of AAV vectors with tropism in the brain as well, and specifically in the Choroid Plexus.
However, Genkin does not teach targeting moieties that are scFv antibody capable of binding one or more receptors on choroid plexus and BBB tissues.
Pardridge teaches that specific antibodies can be engineered for BBB penetration (see title, abstract and section 6, page 1461). Pardridge teaches the use of ScFv antibodies (see Figure 5).
Regarding claim 11, Pardridge also teaches targeting amyloid plaques using ScFv antibodies against Abeta amyloid peptide (see Figure 5). Therefore, Pardridge teaches the generic antibodies for Amyloid Beta, which encompass any species, fragments thereof.
Verhelle teaches specific nanobodies targeting beta-amyloid (see title and abstract). Verhelle specifically teaches a recombinant construct AAV9 comprising a CMV promoter and foreign nucleic acid sequences encoding for nanobodies targeting β-amyloid, Nb11 and FAF Nb1-3 (see Figure 1).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the AAV construct that encodes for and expresses a targeting moiety at the capsid surface as taught by Genkin, with a combination of AAV2/5 or AAV2/8 as taught by Chen, capable of targeting specifically the choroid plexus, and add a foreign DNA sequence encoding for a targeting moiety that is a nanobody targeting β-amyloid, expressed at the surface of the capsid of the vector, as taught by Genkin and modified as taught by Pardridge and Verhelle. One with ordinary skills in the art could have substituted the antibody fragment designed to be expressed at the surface of the viral particle as taught by Genkin with a nanobody targeting specifically the Blood Brain Barrier and using a viral expression vector modified according to Chen to specifically be expressed in neurons. One with ordinary skills in the art, motivated in treating a neural disease, could have performed these modifications with a reasonable expectation of success and would have arrived at the claimed invention.
The following rejection of claim 17 is added in view of Applicant’s election of Species C1, i.e., a tetracycline response element (TRE) in the response filed 06/01/2026:
Claim 17 is rejected under 35 U.S.C. § 103 as being unpatentable over
Genkin (Genkin, D.D. et al. WO 2019/143272 A1 published July 25, 2019), as applied to claims 1-4, 10 and 17 above and in further view of Rose (Rose, S.D. et al. “Integration of Tetracycline regulation into a cell-specific transcriptional enhancer”. The Journal of Biological Chemistry, Vol. 272, No. 21 (1997), pp: 4735-4739).
It is noted that Genkin anticipates all the elements of claim 1. Therefore, claim 1 is also rendered obvious by the combination of Genkin and Rose since:
Regarding claim 1, Genkin teaches an expression vector to be used in liver in vivo in mice (i.e., in mammalian cells) (see Figure 6 and {0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a hGH polyA signal, i.e., a foreign DNA sequence including a human Growth Hormone DNA sequence (see [0098], [0291], [0306]).
Genkin also teaches one or more foreign DNA sequences fused to intracellular or extracellular secretion sequences (see [0018], [0082], [0198], claims 69 and 218).
Genkin teaches that the recombinant expression vector comprises a promoter operably linked to a nucleotide sequence encoding an enzyme having deoxyribonuclease (DNase) activity, i.e., one inserted foreign DNA sequence (see [0011]-[0012]).
Genkin teaches that the recombinant expression vector comprises a chicken β-globin insulator (see [0225]).
Genkin teaches that the recombinant expression vector comprises an AmpR marker, i.e., as foreign DNA sequences that encodes for one or more corresponding proteins (see [0098], [00102]). Genkin teaches that one foreign DNA sequence can be a marker and/or reporter gene encoding for an antibiotic resistance gene, a fluorescent protein (e.g., GFP) or a gene encoding a chemically, enzymatically or otherwise detectable and/or selectable product (e.g., lacZ, aph, etc.) ([0197], [0222]).
Genkin teaches that the recombinant expression vector further comprises a post-transcriptional regulatory element, a woodchuck hepatitis post-transcriptional regulatory element (WPRE) ( see [0029]). Genkin also teaches that the expression vector can comprise an ApoE enhancer that is a hepatic control region (HCR) enhancer, i.e., to control expression of the foreign DNA sequences, including the foreign hGH polyA sequence, and therapeutic genes under a controllable condition (see [0026]).
However, Genkin does not teach the specific element in limitation (1) of claim 17, i.e., a tetracycline response element (TRE) including sequences of “TCCCTATCAGTGATAGAGA” to be included into the vector”.
However, Rose teaches that one can modify promoter and enhancer regions of a specific gene by substituting sequences of the enhancer with tetO sequences, as shown in Figure 1, page 4736, and below:
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As shown above, and in Figure 1, the tetracycline response element (TRE) of sequence “TCCCTATCAGTGATAGAGA” lies between the A and B elements and is added in the new construct before the promoter.
Rose teaches that this substitution confers regulation by exogenous tetracycline and renders the modified enhancer responsive to tetracycline. Moreover, Rose teaches that this substitution leads to a higher level of transactivation compared to native enhancer of the specific gene, 2 to 8 fold higher (see abstract).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the enhancer element controlling the therapeutic gene expression in the construct taught by Genkin, with an enhancer modified with a TRE sequence as taught by Rose. One with ordinary skills in the art motivated in enhancing transactivation level of the therapeutic gene under controllable condition could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Claims 1-4 and 18 are rejected under 35 U.S.C. § 103 as being
unpatentable over Rivera (Rivera, V.M. et al. "Long-term regulated expression of growth hormone in mice after intramuscular gene transfer". Proc.Natl. Acad. Sci. USA, Vol. 96 (1999), pp: 8657-8662; previously cited), in view of Ni (Ni, Y. et al. “Enhanced delivery of human growth hormone across cell membrane by Tat-PTD”. Endocrine, Vol. 46 (2014), pp: 138-147), Kim (Kim, S. et al. US 2008/0153770 A 1; published June 26, 2008; previously cited) and Ho (Ho, Y. et al. “A defined locus control region determinant links chromatin domain acetylation with long-range gene activation”. Molecular Cell, Vol. 9 (2002), pp: 291-302).
Regarding claim 1, Rivera teaches vectors comprising one or more inserted foreign DNA sequences, including human growth hormone (hGH) and another recombinant fusion gene (see Figure 1, reporter gene cassettes TF1, ZG1, ZG2 ), wherein the one or more inserted foreign DNA sequences are fused with intracellular signal/secretion sequences (nuclear localization signals, see page 8658, left column, lines 6-8); a promoter and enhancer, CMV sequences, configured to drive bicistronic transcripts expression of the inserted foreign DNA sequences (see Figure 1 ); the CMV sequence is a combined enhancer/promoter, i.e., a regulatory element (see page 8658, left column, first paragraph), configured to control expression of the hGH and the other recombinant fusion gene under a controllable condition, i.e., addition of rapamycin (see Figure 1 and page 8658, "Results" section, right column, lines 4-7 and Table 1 ).
Examiner interprets that the presence of a secretion signal is present within the hGH DNA sequence since the protein is expressed and secreted (see Figures 2, 4 and 5). However, Rivera is silent about express addition of an extracellular secretion signal and does not teach an insulator configured for stable and safety expression of the one or more inserted foreign DNA sequences and a marker gene, configured to encoding one or more corresponding proteins to indicate the expression of the one or more inserted foreign DNA sequences.
However, Ni teaches that the HIV protein Tat protein transduction domain (Tat-PTD) enhances the absorption of recombinant human growth hormone delivered by oral administration (see title and abstract). Therefore, the Tat-PTD peptide is a delivery signal, a transcellular transport signal, i.e., a secretion signal that can be fused to a recombinant protein for enhance delivery.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date, to have modified the DNA sequence encoding for the recombinant Human Growth Hormone (hGH) and fused a Tat-PTD signal for enhanced transcellular transport and delivery of the recombinant protein once encoded. One with ordinary skills in the art motivated in enhancing the therapeutic effect and bioavailability of the recombinant hGH could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding the claim 1’s limitation “an insulator, configured for stable and safety expression of one or more inserted foreign DNA sequences”, Kim teaches internal promoters in mammalian expression vectors, including retroviral vectors with improved safety and optimal level of transgene expression and vector titers (see abstract).
Kim teaches that a heterologous gene/transgene of interest can encode a
human growth hormone in these vectors (see [0065]). Kim teaches that multiple subunits of a protein encoded by several genes can be arranged in a polycistronic sequence in the vector, separated by one or more IRES elements (see [0066]). Kim teaches that a vector containing a polycistronic sequence may contain the following elements in operable association: internal promoter, heterologous gene (i.e., foreign DNA sequences), an internal ribosome entry site and a second heterologous gene (see [0040]).
Kim teaches vectors comprising polyadenylation sequence, insulator sequences, splicing sites, IRES and other transcriptional and translational effector sequences, i.e., regulatory elements, (see [0014], [0037], [0053] and claim 43).
Kim further teaches that the vectors can be engineered to contain selectable
marker genes (see [0035], [0048], [0057]). Kim also teaches that to reduce any possibility of insertional activation from the internal promoter, insulator sequences may be used to block the activation effect of the internal promoter to nearby genes (see [0053]).
Ho teaches that elements of the locus comprising the hGH gene and especially the hGH locus control region (hGH LCR) (see title and abstract). Ho teaches that in a natural environment the hGH gene is subjected to activation and control via specific determinants, located 14.5 Kb in 5’ region of the promoter, that has critical, non-redundant, and specific role in facilitating promoter trans factor binding and activating hGH-N transcription (see abstract).
Therefore, Ho’s teachings suggest that supplementary regulatory sequences may be needed for “full activation” and optimization of the recombinant hGH gene expression. Ho’s teachings also suggest that hGH gene could be activated, or repressed, by other sequences located within 14.5 Kb of its allocated promoter.
Therefore, it would have been obvious to one with ordinary skills before the
effective filing date of the claimed invention to have modified the vector comprising a polycistronic with one or more foreign DNA sequence, one of which is a human Growth hormone gene as taught by Rivera modified by Ni, with an insulator sequence in the designed polycistronic cassette, as taught by Kim. One with ordinary skills in the art, motivated in selecting for/visualizing cells carrying the vector using a selectable marker as a second foreign DNA sequence, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 2, Rivera teaches AAV vectors (see Table 1, page 8658).
Kim teaches that non-viral vectors such as liposomes, electrically charged lipids and biopolymers, i.e, lipid nanoparticles, can be used, as well as viral vectors can be used, including adeno-associated virus (see [0035]).
Therefore, the elements of claim 2 are rendered obvious by combining the references. The obviousness of the combination of references, Rivera, Ni, Kim and Ho is described above.
Regarding claim 3, Rivera teaches using CMV promoter and enhancer (see page 8653, left column, first paragraph). Kim teaches that CMV enhancer can be used ( [0047]). Kim also teaches a CMV sequence as promoter (see Table 1, [0171], page 14).
Therefore, the elements of claim 3 are rendered obvious by combining the references. The obviousness of the combination of references, Rivera, Ni, Kim and Ho is described above.
Regarding claim 4, Kim teaches the use of a reporter gene within the polycistronic cassette, including GFP or luciferase ( [0048], [0057], [0169]).
Ni teaches a recombinant vector comprising both hGH gene sequence and GFP gene sequence, i.e., pET-22b(+)-Tat-hGH—GFP (see page 139, right column, first paragraph).
Therefore, the elements of claim 4 are rendered obvious by combining the references. The obviousness of the combination of references, Rivera, Ni, Kim and Ho is described above.
Regarding claim 18, Ni teaches that the transcellular transport signal is Tat-PTD (see title and abstract). Ni also teaches that the Tat sequence fused to the N-terminus of the hGH gene is “YGRKKRRQRRR”.
Therefore, the elements of claim 18 are rendered obvious by combining the references. The obviousness of the combination of references, Rivera, Ni, Kim and Ho is described above.
Claim 9 is rejected under 35 U.S.C. § 103 as being unpatentable over Rivera
(Rivera, V.M. et al. "Long-term regulated expression of growth hormone in mice after intramuscular gene transfer". Proc.Natl. Acad. Sci. USA, Vol. 96 (1999), pp: 8657-8662; previously cited), in view of Ni (Ni, Y. et al. “Enhanced delivery of human growth hormone across cell membrane by Tat-PTD”. Endocrine, Vol. 46 (2014), pp: 138-147), Kim (Kim, S. et al. US 2008/0153770 A 1; published June 26, 2008; previously cited) and Ho (Ho, Y. et al. “A defined locus control region determinant links chromatin domain acetylation with long-range gene activation”, Molecular Cell, Vol. 9 (2002), pp: 291-302), as applied to claim 1 and 2 above, and in further view of Åberg (Åberg, N.D. et al. “aspect of Growth Hormone and Insulin-Like Growth Factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain.” The Scientific World Journal, Vol. 6 (2006), pp: 53-80), Shi ( Shi, W. et al. “Insertional mutagenesis of the Adeno-Associated Virus type 2 (AAV2) capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors”, Human Gene Therapy, Vol. 12 (2001), pp: 1697-1711), Merkel (Merkel, S.F. et al. “Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells”, Journal of Neurochemistry, Vol. 140 (2017), pp: 216-230), and Chen (Chen, X. et al. “Different serotypes of Adeno-Associated Virus Vector- and Lentivirus-mediated tropism in Choroid Plexus by intracerebroventricular delivery”, Human Gene Therapy, Vol. 31, No. 7-8 (2020), pp: 440-447).
The rejections of claims 1 and 2 are described above. The combination of references, Rivera, Ni, Kim and Ho, renders the elements of claims 1 and 2 obvious.
Regarding claim 9, Kim teaches that “Virally-mediated gene transfer is attractive due to the efficiency of transfer and high levels of transgene expression, as well as the potential for targeting particular receptors and/or cell types if needed through natural affinity or pseudotyping.” (see [0004]).
However, regarding claim 9, the combination of references does not render the elements of claim 9 obvious, i.e., “ a surface capsule of the expression vector is engineered by inserting a ligand sequence derived from the hGH to bind and/or recognize one or more hGH receptors on Choroid plexus and blood brain barrier (BBB) tissues”.
Åberg teaches that “particularly high expression of GH-R has been observed in the choroid plexus, hippocampus, and the hypothalamus in both rodents [ ] and humans [ ]”. (see page 54, “CNS Expression of Receptors for GH and IGF-I” paragraph, lines 7-8). Therefore, Åberg teaches that GH receptors are abundant and naturally present in the choroid plexus and other parts of the brain.
Shi teaches that the capsid of the AAV vector can be modified using insertional mutagenesis to produce vectors specifically targeted to alternative cell-surface receptors (see title and abstract).
Shi teaches that to obtain cell-specificity and targeting ovarian cancer cells, one can use a 15-amino acid human luteinizing hormone peptide which can bind to its corresponding receptor, the luteinizing hormone receptor naturally present and abundant on the targeted cells’ surface (see abstract).
Thus, Shi’s teaching suggest that one of ordinary skills in the art could use another hormone to target a receptor that is abundant and naturally present on a specific cell or tissue of interest.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the DNA sequence encoding the hGH in the construct taught by Rivera modified with Ni, Kim and Ho, and used a sequence encoding a 15-amino acid hGH peptide to be inserted within the capsid of AAV vector as taught by Shi. One with ordinary skills in the art motivated in targeting the cells of choroid plexus or other tissues in the brain, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding the claim 9’s limitation “recognize one or more hGH receptors on Choroid plexus and blood brain barrier (BBB) tissues” specifically, the combination of references Rivera, Ni, Kim, Ho and Shi does not teach a vector capable of binding the choroid plexus and blood brain barrier specifically.
However, Chen teaches that serotypes AAV2/5 vectors have a tropism for epithelial cells of the choroid plexus (see title and abstract). Chen teaches this tropism after intracerebroventricular injection (see title, abstract). Chen teaches that the combination AAV2/9 exhibit a low efficiency (page 442, right column, first paragraph, and Figure 1).
Merkel teaches that comparing AAV2 to AAV9, AAV2 does not transduce effectively endothelial cells and does not cross the BBB, while AAV9 is more efficient and does penetrate the endothelial barrier without disrupting the BBB integrity (see Abstract).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified and adapted the vector serotype taught by Rivera, Ni, Kim, Ho and Shi, according to the administration method, with a serotype of AAV that is more efficient, using AAV2 in intracerebroventricular administration to target the choroid plexus, or using AAV9 for transducing/binding the BBB, as taught by Merkel. One with ordinary skills in the art, motivated in obtaining vectors optimized and most efficient for specific cargo/payload delivery would have performed these modifications with a reasonable expectation of success and would have arrived at the claimed invention.
Claims 15 and 16 are rejected under 35 U.S.C. § 103 as being unpatentable over Rivera (Rivera, V.M. et al. "Long-term regulated expression of growth hormone in mice after intramuscular gene transfer". Proc.Natl. Acad. Sci. USA, Vol. 96 (1999), pp: 8657-8662; previously cited), in view of Ni (Ni, Y. et al. “Enhanced delivery of human growth hormone across cell membrane by Tat-PTD”. Endocrine, Vol. 46 (2014), pp: 138-147), Kim (Kim, S. et al. US 2008/0153770 A 1; published June 26, 2008; previously cited) and Ho (Ho, Y. et al. “A defined locus control region determinant links chromatin domain acetylation with long-range gene activation”. Molecular Cell, Vol. 9 (2002), pp: 291-302), as applied to claim 1 above, and in further view of Wu (Wu, Y.-H. et al. “Zika Virus infection in hypothalamus causes hormone deficiencies and leads to irreversible growth delay and memory impairment in mice.” Cell Report, Vol 25 (2018), pp: 1537-1547) and Merkel (Merkel, S.F. et al. “Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells”. Journal of Neurochemistry, Vol. 140 (2017), pp: 216-230),
The rejection of claim 1 is described above. The combination of references, Rivera, Ni, Kim and Ho, renders the elements of claim 1 obvious.
Kim teaches that the invention comprises the administration of the composition comprising the expression vector for treating a subject presenting with a genetic disorder, a proliferation disorder, or an infectious disease (see [0021]).
However, the combination of references does not render elements of claims 15 and 16 obvious, i.e., “ the expression vector is used to treat a central nervous system (CNS) disease including brain viral infection by delivering…via crossing the BBB.” (claim 15).
Wu teaches that the Zika virus infection can cause brain disease such as microcephaly in the fetus and has a detrimental effect on growth and neurodevelopment of children born with the disease (see title and abstract).
Wu teaches that acute disease presents with a decrease of hGH expression, causing growth delays (see abstract, and Figure 1).
Wu teaches that using GH as therapy can partially rescue growth delay (see page 1540, right column, “Growth delay was partially rescued by Hormone therapy” section; Figures 4D and 4F). Wu teaches that even though the hormones levels in the serum over the long-term are increased in the infected individual, the effect of postnatal deficiencies are still observed leading to microcephaly (skull diameter; see Figure 7D) and therefore neurodevelopmental delays affecting learning and memory (page 1544, left column, “Discussion” section).
Merkel teaches that using the AAV9 serotype as a vector is more efficient than other type AAV2. Merkel also teaches that AAV9 vector does penetrate the endothelial barrier without disrupting the BBB integrity (see Abstract).
Thus, Merkel’s teachings suggest that AAV9 vector represents a safe and effective solution to target the blood brain barrier tissues.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have used the construct expression a recombinant hGH taught by Rivera, Ni, Kim and Ho and adopted the AAV9 serotype for vector as suggested by Merkel, to treat a brain infectious disease such as Zika virus infection taught by Wu. One with ordinary skills in the art motivated in targeting the effect of an acute infection leading to growth and neurodevelopmental delays could have used an AAV9 construct comprising hGH gene as therapeutic replacement capable of targeting the BBB. One with ordinary skills in the art could have made this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding claim 16 and a method of delivery that is intravenous injection, nasal spray, inhalation, liquid and/or tablet, eye drop, or combination thereof, Kim teaches that the methods of administration of the expression vector can be intravenous, that pulmonary administration can be by the use of an inhaler or nebulizer and formulation with an aerosolizing agent (see [0088]).
Therefore, the elements of claim 16 are rendered obvious by combining the references. The obviousness of the combination of references, Rivera, Ni, Kim, Ho, Wu and Merkel is described above.
Allowable Subject Matter
SEQ ID Nos: 59 and 60 are not found in prior art. SEQ ID NO: 58 is 100% identical to a significantly larger sequence found in Xie (US 10,563,207 B2, published February 18, 2020) in a sequence identified as SEQ ID NO: 50. However, the small portion of Xie’s sequence that encompasses instant SEQ ID NO: 58 is not identified as a possible chromatin insulator sequence.
Claim 6 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-5, 7-11 and 15-18 are rejected. Claim 6 is objected to.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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