Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group II (Claims 12, 18-19, 24, and 49; drawn to an expression vector) in the reply filed on May 7, 2024, is acknowledged.
Rejoinder
The election requirement for Groups I and III has been reconsidered in view of the prior art. Groups I and III have been rejoined.
Claims 28, 30, 32, 37, 39, 42-43, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups III and IV), there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on June 9, 2025, have been acknowledged. Claims 7-8, 10-11, 13-17, 20-23, 26-27, 29, 31, 33-36, 38, 40-41, 44-47, and 50 were cancelled. Claims 3-6, 9, 12, 18-19, 24, 25, 28, 30, 32, 37, 39, 42-43, 48-49 were amended. In light of the Applicant’s elected invention and rejoinder of Groups I and III, claims 28, 30, 32, 37, 39, 42-43, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-6, 9, 12, 18-19, 24-25, and 49 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 62/908,966, filed on October 1, 2019. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-6, 9, 12, 18-19, 24-25, and 49 receive domestic benefit from U.S. provisional application No. 62/908,966, filed on October 1, 2019.
Information Disclosure Statement
The information disclosure statements (IDS) filed on March 31, 2022, and September 16, 2022, have been considered.
Specification
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Pages 2-4, 6-8, 10-14, 21-25, and 46-48 recites sequences without the corresponding SEQ ID NOs.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
The disclosure is objected to because of the following informalities: The sequence for P1 and the sequence for E2 are the same. The priority document 62/908,966 uses a different sequence for E2. As such, E2 should be fixed to recite the correct sequence and if this sequence is not in the sequence listing, it should be added.
Appropriate correction is required.
The attempt to incorporate subject matter into this application by reference to “nucleotides 83,518,714 to 83,521,414 of murine chromosome 15 or a corresponding portion of a human chromosome” is ineffective because there is no canonical sequence for this region of murine chromosome 15 or a corresponding portion of a human chromosome as there are a multitude of different mouse strains and humans with differences in nucleotide sequences from mutations, such as insertions, deletions, chromosomal rearrangements, etc. that would change the resulting sequence. Therefore, this reference point represents a specific reference to a vague entity that is a moving object depending on the murine strain or human and does not represent a specific sequence
The incorporation by reference will not be effective until correction is made to comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to meet any outstanding objection, rejection, or other requirement imposed by the Office, the correction must be made within any time period set by the Office for responding to the objection, rejection, or other requirement for the incorporation to be effective. Compliance will not be held in abeyance with respect to responding to the objection, rejection, or other requirement for the incorporation to be effective. In no case may the correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated by reference must be accompanied by a statement that the material being inserted is the material incorporated by reference and the amendment contains no new matter. 37 CFR 1.57(g).
Claim Objections
Claim 6 is objected to for an improper incorporation by reference. The attempt to incorporate subject matter into this application by reference to “nucleotides 83,518,714 to 83,521,414 of murine chromosome 15 or a corresponding portion of a human chromosome” is ineffective because there is no canonical sequence for this region of murine chromosome 15 or a corresponding portion of a human chromosome as there are a multitude of different mouse strains and humans with differences in nucleotide sequences from mutations, such as insertions, deletions, chromosomal rearrangements, etc. that would change the resulting sequence. Therefore, this reference point represents a specific reference to a vague entity that is a moving object depending on the murine strain or human and does not represent a specific sequence
The incorporation by reference will not be effective until correction is made to comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to meet any outstanding objection, rejection, or other requirement imposed by the Office, the correction must be made within any time period set by the Office for responding to the objection, rejection, or other requirement for the incorporation to be effective. Compliance will not be held in abeyance with respect to responding to the objection, rejection, or other requirement for the incorporation to be effective. In no case may the correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated by reference must be accompanied by a statement that the material being inserted is the material incorporated by reference and the amendment contains no new matter. 37 CFR 1.57(g).
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.
Claims 5-6, 9, 18-19, 24, and 49 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.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)). Claim 6 recites “nucleotides 83,518,714 to 83,521,414 of murine chromosome 15 or a corresponding portion of a human chromosome”. As stated supra, there is no canonical sequence for this region of murine chromosome 15 or a corresponding portion of a human chromosome as there are a multitude of different mouse strains and humans with differences in nucleotide sequences from mutations, such as insertions, deletions, chromosomal rearrangements, etc. that would change the resulting sequence. Therefore, this reference point represents a specific reference to a vague entity that is a moving object depending on the murine strain or human and does not represent a specific sequence. Therefore, depending on the mouse or human sequence being examined, the sequence will be different.
Claims 5, 9, 18-19, and 24 claim sequences associated with MPP01 (P1) and/or E2. However, both P1 and E2 are represented by SEQ ID NO:1 even though they are considered separate regulatory elements as P1 is a proximal promoter and E2 is an enhancer. Furthermore, the priority document 62/908,966 uses a different sequence for E2 than SEQ ID NO: 1. As such, the P1 and E2 are considered to have separate sequences and have been incorrectly identified as having the same sequence.
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.
Claim 18 is 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.
Claim 18 is dependent on cancelled claim 17 and should be amended to depend on a non-cancelled claim.
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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-6, 12, and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. The claims recite a naturally occurring polypeptide or DNA segment encoding an isolated translocator protein (TSPO) promoter (claims 1-6) and an expression vector comprising the promoter (claims 12 and 24).
This judicial exception is not integrated into a practical application because the fact of purification or isolation alone is inadequate to demonstrate a marked structural difference and the vector (in regards to the isolated nucleic acid molecule) does not add a meaningful limitation. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Applicant is directed to the 2014 Interim Guidance on Patent Subject Matter Eligibility (79 FR 74618), which is found at: http://www.uspto.gov/patent/laws-and-regulations/examination-policy/2014-interim-guidance-subject-matter-eligibility-0; as well as the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
This guidance supersedes M.P.E.P. § 2106, and previous guidance for patent eligible subject matter in view of Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. __, 132 S.Ct. 1289, 101 USPQ2d 1961 (2012) (“Mayo”) and Molecular Pathology v. Myriad Genetics Inc, 12-398 (2013) (“Myriad”). This guidance supersedes the prior guidance issued by the USPTO on March 4th, 2014, and supplements the examination instructions issued on June 25th, 2014 in view of Alice Corp. v. CLS Bank Int'l, 110 USPQ2d 1976 (2014).
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, the claimed invention is directed to a statutory class of invention, i.e., a product.
In regard to Step 2A, prong one, instant claims are directed to an isolated promoter fragment sufficient to direct expression of a downstream polynucleotide in a microglial cell (claims 1-4), wherein the fragment has 85% sequence identity to MPP01-MPP04 (SEQ ID NOs: 1-2 and 6-7) (claim 5) or wherein the full-length promoter comprises nucleotides 83,518,714 to 83,521,414 of murine chromosome 15 or a corresponding portion of a human chromosome (claim 6), an expression vector comprising the promoter fragment (claim 12), or an expression vector comprising a regulatory element comprising a polynucleotide sequence with 85% sequence identity to MPP01-MPP04 (SEQ ID NOs: 1-2 and 6-7). Regarding claims 1-4 and 12, Rashid et al. (Gene Regulatory Mechanisms 1861: 1119-1133. 2018) evidences that many fragments of the mouse TSPO promoter that comprise at least regions -125-+79 are sufficient to drive expression of a downstream gene in microglial cells (BV-2 cells) (abstract, page 1120, column 1, paragraph 4-page 1121, column 1, paragraph 2, and Figure 1). Furthermore, Rashid evidences that the LPS induced activity was abolished when sequences between −593 and −520 bp were deleted (Fig. 2), implying that these sequences contain cis-acting regulatory elements that drive TSPO expression in response to pro-inflammatory stimuli (page 1125, column 1, paragraph 1). As shown by Figure 1 of Rashid, promoter fragments of 1534 nucleotides (considered to fall within about) is sufficient to drive expression in microglial cells.
Regarding claims 5 and 24, NCBI (AY383615.1, Homo sapiens benzodiazapine receptor (peripheral) (BZRP) gene; also known as TSPO) evidences that this gene contains a sequence that has 97.5% sequence identity to MPP01. Therefore, a fragment of the human sequence could be isolated.
Regarding claim, as stated in the 112b rejection above, although the sequence associated with nucleotides 83,518,714 to 83,521,414 of murine chromosome 15 or a corresponding portion of a human chromosome are not disclosed, this would involve isolation of a fragment of the promoter from a naturally occurring chromosome from murine or human subjects.
Although the claimed nucleic acid has a different structural characteristic than the naturally occurring human TSPO gene, because the chemical bonds at each end were severed in order to isolate it from the chromosome on which it occurs in nature; however, the human TSPO gene falls within the 85% sequence identity required of claim 5. Therefore, the natural gene falls within the 85% sequence identity to SEQ ID NO: 1 (MPP01). The claimed nucleic acid has no different functional characteristics, i.e., it encodes a TSPO promoter as does the natural gene. Under the holding of Myriad, this isolated but otherwise unchanged nucleic acid is not eligible because it is not different enough from what exists in nature to avoid improperly tying up the future use and study of naturally occurring TSPO promoters. In other words, the claimed nucleic acid is different, but not markedly different, from its natural counterpart in its natural state (TSPO promoter sequences on chromosome 22), and thus is a “product of nature” exception. Accordingly, the claims are directed to an exception (Step 2A, prong one: YES).
In regard to Step 2A, prong two, instant claims are directed to an isolated promoter fragment (claims 1-6), an expression vector comprising the promoter fragment (claim 12), or an expression vector comprising a regulatory element comprising a polynucleotide sequence with 85% sequence identity to MPP01-MPP04 (SEQ ID NOs: 1-2 and 6-7). With respect to Step 2A, prong two, limitations that may be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Improvements to another technology or technical field.
Improvements to the functioning of the computer itself.
Applying the judicial exception with, or by use of, a particular machine.
Effecting a transformation or reduction of a particular article to a different state or thing
Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application.
Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
With respect to Step 2A, prong two, limitations that were found not to be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Adding the words ‘‘apply it’’ (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well understood, routine and conventional activities previously known to the industry
Adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea
Generally linking the use of the judicial exception to a particular technological environment or field of use.
In regard to Step 2A, prong two, instant claims do not recite additional elements or a combination of elements in the claims other than the natural product itself. Specifically, claim 1-6 recite an isolated TSPO promoter fragment. As discussed above, these claims read directly on a natural product. Regarding claims 12 and 24, claim 12 recites “an expression vector comprising the promoter fragment of claim 1” and claim 24 recites “An expression vector comprising a regulatory element comprising a polynucleotide sequence having at least 85% identity”. As such, claims 12 and 24 are considered to encompass the full length promoter as the comprising language encompasses the fragment and additional nucleotides, such as the rest of the full length promoter. Furthermore, claims 12 and 24 recite an “expression vector.” However, placing nucleic acids in an “expression vector” is claimed with such a high degree of generality it encompasses expression systems of a natural host cell. (Step 2A, prong two: NO)
Finally, in regard to Step 2B, does the claim recite additional elements that amount to significantly more than the judicial exception. Regarding claims 1-6, the isolated promoter fragment reads on a natural product. Claims 1-6 don’t include any additional elements. Regarding claims 12 and 24, they recite generic expression vectors which were well-understood, routine and conventional in the art at the time of the invention. Viewed as a whole, these additional claim elements do not provide meaningful limitations to transform the natural product into a patent eligible composition.
Therefore, claims 1-6, 12, and 24 add no additional elements that integrate the judicial exception into a practical application than the “product of nature” itself. Thus, instant claims do not amount to significantly more than the judicial exception itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Claims 25 and 49 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. Claims 25 and 49 have a broadest reasonable interpretation that encompasses a cell that comprises the naturally occurring TSPO promoter which is not markedly different from its naturally occurring counterpart. This judicial exception is not integrated into a practical application because the natural product is not linked to a particular technology. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations are well-understood, routine and conventional in cell biology.
The two part test is briefly summarized here: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, Claims 25 and 49 are drawn to a composition of matter-a cell.
In regard to Step 2A prong one, Claims 25 and 49 are drawn to a nature-based product which is not markedly different from its naturally occurring counterpart. Specifically, Claims 25 and 49 are directed to a cell comprising the expression vector of claim 12. As stated supra, claims 12 and 24 are considered to encompass the full length promoter as the comprising language encompasses the fragment and additional nucleotides, such as the rest of the full length promoter. However, placing nucleic acids in an “expression vector” is claimed with such a high degree of generality it encompasses expression systems of a natural host cell. Thus, naturally occurring cells comprising a full length TSPO promoter would fall within the limitations of claims 25 and 49. Because instant claims are directed to a nature-based product, i.e., cells, the nature-based product is analyzed to determine whether it has markedly different characteristics from any naturally occurring counterpart(s) in their natural state. Rashid et al. (Gene Regulatory Mechanisms 1861: 1119-1133. 2018) evidences that the full-length mouse TSPO promoter (-2733) is sufficient to drive expression of a downstream gene in microglial cells (BV-2 cells) (abstract, page 1120, column 1, paragraph 4-page 1121, column 1, paragraph 2, and Figure 1).
Thus, instant claims encompass host cells that are identical (no difference in structural or functional characteristics) to naturally occurring cells comprising the full-length TSPO promoter. Because there is no difference between the claimed and naturally occurring cells, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. Accordingly, instant claims are directed to a judicial exception.
In regard to Step 2A prong two, the judicial exception is not integrated into a practical application. In particular, Claim 12 recites no additional elements to integrate the claimed cell into a practical application. Although Claim 49 recites a pharmaceutical composition comprising the cell, no additional element is identified as part of the composition other than the cell. Therefore, the broadest reasonable interpretation of the pharmaceutical composition is that it can comprise the cell by itself. Therefore, this claim still reads on a naturally occurring cell.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated supra, Claim 25 recites no additional elements to the cell and claim 49 recites a pharmaceutical composition that broadly encompasses the cell by itself.
Therefore, Claims 25 and 49 are directed to a natural cell product, that is not markedly different from its natural counterpart, is not integrated into a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 12, 25, and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rashid et al. (Gene Regulatory Mechanisms 1861: 1119-1133. 2018).
Regarding claims 1, 12, 25, and 49, Rashid teaches that they cloned the murine TSPO promoter into the pGL4.10 luciferase plasmid vector and functionally characterized it in transfected BV-2 cells (a microglia cell) (abstract, page 1120, column 1, paragraph 4-page 1121, column 1, paragraph 2, and Figure 1). As can be seen in Figure 1, the promoter drives expression of the luciferase gene in BV-2 microglial cells.
Regarding claim 49, although Claim 49 recites a pharmaceutical composition comprising the cell, no additional element is identified as part of the composition other than the cell. Therefore, the cell cultures of BV-2, RAW-264.7, and ARPE-19 cells are considered to fall within the pharmaceutical composition of claim 49.
Regarding claim 2, Rashid teaches that the LPS induced activity was abolished when sequences between −593 and −520 bp were deleted (Fig. 2), implying that these sequences contain cis-acting regulatory elements that drive TSPO expression in response to pro-inflammatory stimuli (page 1125, column 1, paragraph 1). Rashid teaches promoter fragments that include this sequence (Figure 1).
Regarding claims 3-4, As shown by Figure 1 of Rashid, promoter fragments of 1534 nucleotides (considered to fall within about) is sufficient to drive expression in microglial cells.
Claims 1-5, 12, 24-25, and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Batarseh et al. (Biochimica et Biophysica Acta 1819: 38-56. 2012), as evidenced by Pozzo et al. (Int. J. Mol. Sci. 20: 1-21. 2019), Rashid et al. (Gene Regulatory Mechanisms 1861: 1119-1133. 2018), and GenBank (Z82214.23).
Regarding claims 1, 12, 24-25, and 49, Batarseh teaches that they identified, cloned, and functionally characterized the TSPO promoter in poor-in-TSPO hormone-dependent, non-aggressive MCF-7 cells and rich-in-TSPO hormone independent, aggressive, and metastatic MDA-MB-231 breast cancer cells using pGL3 reporter vectors. Deletion analysis indicated that the region from −121 to +66, which contains five putative regulatory sites known as GC boxes, was sufficient to induce reporter activity up to 24-fold in MCF-7 and nearly 120-fold in MDA-MB-231 cells. Batarseh generated a multitude of promoter fragments as part of the deletion analysis (abstract, page 39, column 1, paragraph 3-column 2, paragraph 3 and Figure 2). As this promoter drives expression of non-endogenous nucleotides, the promoter would necessarily be a fragment of the larger TSPO gene. Therefore, the full length promoter used by Batarseh would also be a promoter fragment.
Regarding claim 49, although Claim 49 recites a pharmaceutical composition comprising the cell, no additional element is identified as part of the composition other than the cell. Therefore, the cell cultures of MCF-7 and MDA-MB-231 cells are considered to fall within the pharmaceutical composition of claim 49.
Batarseh does not assess their promoter fragments in microglial cells. However, Pozzo evidences that the proximal promoter of the human TSPO gene corresponds to a roughly 1000 base pair region that is sufficient to drive expression in C20 microglial cells (Figure 6). Therefore, the promoter fragments of Batarseh that contain this proximal promoter are considered to direct expression of a polynucleotide in microglial cells. Furthermore, the full length wild type promoter is shown to drive expression of TSPO in C20 microglial cells (Figure 6). Furthermore, Batarseh teaches that GC boxes 1-5 are essential for promoter activity and are conserved between mouse and human TSPO promoters (Sp.1-4 is the conserved region in mice) (Figure 3). Rashid evidences that Sp 1-4 were crucial for promoter activity in microglial cells (Figure 4). Therefore, as these are conserved regions in mouse and human TSPO promoters, one can conclude that the GC boxes 1-5 are essential for promoter activity in microglial cells in humans and as long as the -121-+66 region comprising these GC boxes are found in the promoter fragment, the promoter will be able to drive expression of a downstream gene in a microglial cell.
Regarding claim 2, Pozzo evidences that there is an NF-κB binding site in the promoter that results in activation from IL-1β stimulation near the -350 position (page 9, paragraph 3-page 10, paragraph 2 and Figures 6-7).
Regarding claims 3-4, Batarseh teaches a promoter fragment that is 1451 and 1087 nucleotides in length (considered to fall within about).
Regarding claim 5, Batarseh teaches that the promoter sequence is from GenBank accession number Z82214.23. GenBank (Z82214.23) evidences that this sequence comprises a sequence with 97.5% sequence identity to MPP01 (SEQ ID NO: 1).
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, 12, 25, and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, and 9 of copending Application No. 17/764,917 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 12, and 25, ‘917 claims a method of treating a subject having Alzheimer’s disease comprising administering a cell comprising an expression vector comprising a TSPO promoter (claims 1, 6-7, and 9). As this promoter drives expression of non-endogenous nucleotides, the promoter would necessarily be a fragment of the larger TSPO gene. Although this is a method, the method comprises the product as claimed in the instant application.
Regarding claim 49, as the method involves administering the cell to a patient, it would necessarily be a pharmaceutical composition.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 12, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, and 9 of copending Application No. 17/764,917, as applied to claim 1 and 12 above and further in view of Batarseh et al. (Biochimica et Biophysica Acta 1819: 38-56. 2012) and Rashid et al. (Gene Regulatory Mechanisms 1861: 1119-1133. 2018), as evidenced by Pozzo et al. (Int. J. Mol. Sci. 20: 1-21. 2019) and GenBank (Z82214.23).
The teachings of ‘917 are as discussed above.
‘917 is silent as to the sequence of the TSPO promoter.
Batarseh teaches a multitude of TSPO promoter sequences that are sufficient to drive expression of a downstream gene in cells. Batarseh teaches that they identified, cloned, and functionally characterized the TSPO promoter in poor-in-TSPO hormone-dependent, non-aggressive MCF-7 cells and rich-in-TSPO hormone independent, aggressive, and metastatic MDA-MB-231 breast cancer cells using pGL3 reporter vectors. Deletion analysis indicated that the region from −121 to +66, which contains five putative regulatory sites known as GC boxes, was sufficient to induce reporter activity up to 24-fold in MCF-7 and nearly 120-fold in MDA-MB-231 cells. Batarseh generated a multitude of promoter fragments as part of the deletion analysis (abstract, page 39, column 1, paragraph 3-column 2, paragraph 3 and Figure 2). As this promoter drives expression of non-endogenous nucleotides, the promoter would necessarily be a fragment of the larger TSPO gene. Therefore, the full length promoter used by Batarseh would also be a promoter fragment.
Batarseh does not assess their promoter fragments in microglial cells. Batarseh does teach that GC boxes 1-5 are essential for promoter activity and are conserved between mouse and human TSPO promoters (Sp.1-4 is the conserved region in mice) (Figure 3).
Rashid teaches that Sp 1-4 were crucial for promoter activity in microglial cells (Figure 4). Therefore, as these are conserved regions in mouse and human TSPO promoters, one can conclude that the GC boxes 1-5 are essential for promoter activity in microglial cells in humans and as long as the -121-+66 region comprising these GC boxes are found in the promoter fragment, the promoter will be able to drive expression of a downstream gene in a microglial cell.
It would have been obvious to a person skilled in the art to use any of the promoter fragments of Betarseh that were successfully shown to drive expression of a gene to drive expression of a gene to treat Alzheimer’s in microglial cells in the method of ‘917. Alzheimer’s is known to effect microglial cells and as claimed by ‘917, TSPO is a known microglial promoter and Rashid shows that TSPO promoter fragments are also successful in driving expression in mouse microglial cells. Although Betarseh didn’t examine their promoters in microglial cells. As identified by Betarseh and Rashid, the GC box region is conserved between mouse (Sp 1-4) and human (GC boxes 1-5) TSPO genes and is critical from promoter expression. Therefore, it would be well understood that promoter sequences that contain this conserved region would drive expression in microglial cells, providing a reasonable expectation of success that the promoter fragments of Betarseh would also drive expression in microglial cells.
Regarding claim 2, Pozzo evidences that there is an NF-κB binding site in the promoter that results in activation from IL-1β stimulation near the -350 position (page 9, paragraph 3-page 10, paragraph 2 and Figures 6-7).
Regarding claims 3-4, Batarseh teaches a promoter fragment that is 1451 and 1087 nucleotides in length (considered to fall within about).
Regarding claims 5 and 24, Batarseh teaches that the promoter sequence is from GenBank accession number Z82214.23. GenBank (Z82214.23) evidences that this sequence comprises a sequence with 97.5% sequence identity to MPP01 (SEQ ID NO: 1).
This is a provisional nonstatutory double patenting rejection.
Claim 1, 12, 25, and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 51 of copending Application No. 18/401,135 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘135 claims a method of regulating expression of exogenous genes within engineered microglia comprising transducing microglia progenitors with viral vectors encoding a gene of interest under the control of the TSPO promoter (claim 51). As this promoter drives expression of non-endogenous nucleotides, the promoter would necessarily be a fragment of the larger TSPO gene. Although this is a method, the method comprises the product as claimed in the instant application.
Regarding claim 49, although Claim 49 recites a pharmaceutical composition comprising the cell, no additional element is identified as part of the composition other than the cell. Therefore, the engineered microglial cells are considered to fall within the pharmaceutical composition of claim 49.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 12, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 51 of copending Application No. 18/401,135, as applied to claim 1 and 12 above and further in view of Batarseh et al. (Biochimica et Biophysica Acta 1819: 38-56. 2012) and Rashid et al. (Gene Regulatory Mechanisms 1861: 1119-1133. 2018), as evidenced by Pozzo et al. (Int. J. Mol. Sci. 20: 1-21. 2019) and GenBank (Z82214.23).
The teachings of ‘135 are as discussed above.
‘135 is silent as to the sequence of the TSPO promoter.
Batarseh teaches a multitude of TSPO promoter sequences that are sufficient to drive expression of a downstream gene in cells. Batarseh teaches that they identified, cloned, and functionally characterized the TSPO promoter in poor-in-TSPO hormone-dependent, non-aggressive MCF-7 cells and rich-in-TSPO hormone independent, aggressive, and metastatic MDA-MB-231 breast cancer cells using pGL3 reporter vectors. Deletion analysis indicated that the region from −121 to +66, which contains five putative regulatory sites known as GC boxes, was sufficient to induce reporter activity up to 24-fold in MCF-7 and nearly 120-fold in MDA-MB-231 cells. Batarseh generated a multitude of promoter fragments as part of the deletion analysis (abstract, page 39, column 1, paragraph 3-column 2, paragraph 3 and Figure 2). As this promoter drives expression of non-endogenous nucleotides, the promoter would necessarily be a fragment of the larger TSPO gene. Therefore, the full length promoter used by Batarseh would also be a promoter fragment.
Batarseh does not assess their promoter fragments in microglial cells. Batarseh does teach that GC boxes 1-5 are essential for promoter activity and are conserved between mouse and human TSPO promoters (Sp.1-4 is the conserved region in mice) (Figure 3).
Rashid teaches that Sp 1-4 were crucial for promoter activity in microglial cells (Figure 4). Therefore, as these are conserved regions in mouse and human TSPO promoters, one can conclude that the GC boxes 1-5 are essential for promoter activity in microglial cells in humans and as long as the -121-+66 region comprising these GC boxes are found in the promoter fragment, the promoter will be able to drive expression of a downstream gene in a microglial cell.
It would have been obvious to a person skilled in the art to use any of the promoter fragments of Betarseh that were successfully shown to drive expression of a gene to drive expression of a gene in microglial cells in the method of ‘135. Rashid shows that TSPO promoter fragments are also successful in driving expression in mouse microglial cells. Although Betarseh didn’t examine their promoters in microglial cells. As identified by Betarseh and Rashid, the GC box region is conserved between mouse (Sp 1-4) and human (GC boxes 1-5) TSPO genes and is critical from promoter expression. Therefore, it would be well understood that promoter sequences that contain this conserved region would drive expression in microglial cells, providing a reasonable expectation of success that the promoter fragments of Betarseh would also drive expression in microglial cells.
Regarding claim 2, Pozzo evidences that there is an NF-κB binding site in the promoter that results in activation from IL-1β stimulation near the -350 position (page 9, paragraph 3-page 10, paragraph 2 and Figures 6-7).
Regarding claims 3-4, Batarseh teaches a promoter fragment that is 1451 and 1087 nucleotides in length (considered to fall within about).
Regarding claims 5 and 24, Batarseh teaches that the promoter sequence is from GenBank accession number Z82214.23. GenBank (Z82214.23) evidences that this sequence comprises a sequence with 97.5% sequence identity to MPP01 (SEQ ID NO: 1).
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631