Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-43 are currently pending in this application.
Election/Restrictions
Applicant's election without traverse of Group I, claims 1-27, in the reply filed on Jan. 27, 2026 is acknowledged, as well as Applicant's election of the target sequence species SEQ ID NO: 5. Claims 28-43 as amended are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected subject matter, there being no allowable generic or linking claim. Claims 1-27 have been considered on the merits.
Benefit of Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. US 63/141,344 and 63/176,813, each fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for some of the instant claims due to the delivering of “one or more viral vectors” in claim 1 when (1) there is only support for multiple viral vectors that are scAAV (self-complementary) (US 63/141,344 at claim 16 and in 63/176,813 at pg. 18 and 20 and claim 16); (2) no support for the scope of a meganuclease “comprising” any of SEQ ID NO: 1-3 (instant claim 8); (3) no support for the scope of a carrier “configured” for any injection (instant claim 16), (4) no support for the scope of any intramuscular injection (instant claim 18), and (5) no support in US 63/141,344 for claims instant 19-27. Therefore the earliest effective filing date of instant claims 1-2, 6-9, and 13-27 is Jan. 25, 2022; and the earliest effective filing date of instant claims 3-5 and 10-12 is Jan. 25, 2021.
Claim Objections
Claim 24 recites a group, which as opposed to being drafted with standard Markush language, uses nonstandard language which is suggested to be rewritten with “consisting” before the “of” or alternatively as “selected from JQ1, birabresib, molibresib, apabetalone, ZEN-3694, BMS-986158, or INC-B057643.” Appropriate correction is requested.
Claim Interpretation
In the claims, the phrase “reducing or eliminating latent Herpes simplex virus type 1 (HSV-1) reactivation” is interpreted as meaning, upon challenge with HSV-1 reinfection, eliminating or producing reduced shedding, HSV-1 viral loads, HSV-1 lytic behaviors, and/or lesions as compared to a negative control, such as using an in vivo assay (e.g., BET-inducement) or a ganglion explant assay, e.g., using a superior cervical ganglion (SCG) or trigeminal ganglion (TG) (see e.g., instant specification, published as US20240301372A1, at [0016]-[0017], [0075]-[0076], Examples 1-2). Further, the term “eliminating” as defined in the instant specification is limited to completely preventing (removal) the occurrence of reactivation upon challenge, which encompasses completely halting HSV-1 reactivation even after replication/assembly of a latent HSV-1 has begun so long as all pertinent signs of reactivation remain undetectable, such as host cell lysis, shedding, and virus load (id.; [0086]).
In the claims, the term “delivering” is interpreted as administering the one or more viral vectors comprising the one or more sequences encoding the one or more HSV-1-specific meganuclease(s) into the cell (e.g., of a subject), i.e., delivering inside of the cell. When the cell is in a subject, the delivering may be more complex/multistage by including inchoate delivery by a method or route placing the vector inside the subject which eventually conveys the vector in proximity of the cell and then the proximate delivering is achieved once the viral vector enters said cell, such as initiating delivering via a cell transfer (instant pg. 26, 2nd para.) or an injection as in claims 17 and 18 but not accomplishing delivering until the entry of the injected AAV virion into the cell, e.g., via receptor-mediated endocytosis.
The term “viral vector” is interpreted as including a virus particle or virion comprising a nucleic acid as well as just a viral nucleic acid or engineered nucleic acid vector, e.g., an AAV vector nucleic acid (see instant [0054]).
In the claims, the term “HSV-1-specific meganuclease,” while not defined by the instant application or claims, is interpreted to mean any meganuclease (e.g., naturally occurring or engineered) that cleaves an internal DNA sequence (i.e., endonucleolytically) specific, but not necessarily exclusive, to a HSV-1 genome(s) based on an at least 12 base pair (bp) recognition site comprising the cleavage site (see instant [0046], [0058]; Castro et al., Int J Mol Sci 22: 10355 (2021) at 2. Meganucleases, pg. 2-5, Fig. 1). This specificity can stringently require 100% sequence identity to the optimal recognition site sequence or may tolerate mismatches, e.g., due to central base pair wobble; and artificial meganucleases may exhibit greater sequence tolerance/promiscuity (e.g., I-LtrI variant E184D or recombinant LAGLIDADG meganuclease chimeras) (Baxter et al., Nucleic Acids Res 40: 7985-8000 (2012) at Fig. 5-6; McMurrough et al., Nucleic Acids Res 46: 11990-12007 (2018) at abstract).
In the claims, the term “self-complementary adeno-associated virus” abbreviated as “scAAV” is interpreted as having its ordinary meaning of an adeno-associated virus (i.e., virion) having a genomic DNA molecule capable of (1) forming an intramolecular double-stranded DNA form based on internal base pairing (i.e., a closed terminal hairpin), (2) transgene expression without de novo second strand synthesis or intermolecular annealing, possibly providing greater efficiency than an ssAAV comparator (instant [0111]; [0078]; McCarty, Mol Ther 16: 1648-56 (2008) at abstract).
In claim 4, the term a “combination thereof” under a broadest reasonable interpretation is interpreted as not encompassing a hybrid serotype of AVV-Rh10, AAV8, and/or AAV1; but rather a plurality of different virus types, each having the adeno-associated virus serotype selected from AVV-Rh10, AAV8, and AAV1.
In claim 9, the limitation of “configured to target one or more sequences as set forth in SEQ ID NOs: 4-6” is interpreted as limiting each of the meganucleases individually as oppose to the meganuclease(s) collectively.
In claim 12, the term “different” with regard to species of scAAV encompasses wherein virus vector genomes differ by a single nucleotide, such as within a meganuclease coding region (including a silent mutation) or unrelated to any meganuclease (e.g., within vector backbone), and thus encompassing different genome structures having no functional difference or consequence.
In claim 15, the term a “combination thereof” under a broadest reasonable interpretation is interpreted as not encompassing a hybrid/combo cell type; but rather both of the different ganglia types.
In claim 16, the preposition ‘with’ is interpreted to mean “in combination, accompaniment, presence of or as a participant”; as oppose to meaning a “means, cause or instrumentality” of the delivering.
In claims 19-22, the term “administering” is interpreted as encompassing merely contacting the HSV-1-infected cell with a BET protein inhibitor independently of the infecting of that cell with viral vector, even in view of dependent claim 22 requiring this may occur simultaneously or concurrently (i.e., “concomitant with”).
In claim 24, the term “INC-B057643” is interpreted as being synonymous with “INCB057643.”
112(f) - 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.
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) are:
in claim 6, the phrase “configured to induce one or more DNA double strand breaks (DSB)”;
in claim 7, the phrase “configured to target one or more HSV-1 genes essential for replication”;
in claim 9, the phrase “configured to target one or more sequences”; and
in claim 16, the phrase “configured for injection.”
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(a) - Written Description
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 1-27 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. Claim 1 is directed to a method for reducing or eliminating latent Herpes simplex virus type 1 (HSV-1) reactivation by delivering into an HSV-1-infected cell a viral vector(s) encoding an HSV-1-specific meganuclease(s). The claim is broad in at least that:
(1) “eliminating” requires complete prevention of any detectable HSV-1 reactivation in the cell, as defined by the instant specification ([0086]),
(2) delivering is unlimited as to any minimum/effective amount of the viral vector(s) and/or HSV-1-specific meganuclease(s),
(3) one or more viral vector(s) without limit,
(4) an HSV-1-specific DNA target molecule need not be altered, and
(5) none of the method steps (e.g., delivering and ability of encoding) expressly requires/results in expression of any meganuclease in the infected cell and no such associated requisite structure is recited (e.g., a promoter or other regulatory element), and
(6) the meganuclease genus comprises members configured to target any HSV-1 specific sequence, two or more genes, and/or non-gene sequences.
The prior art teaches using homing endonucleases (HE) generally to stimulate targeted genomic editing in cells and mice, such as engineered meganucleases (e.g., of the LAGLIDADG family like I-SceI and I-CreI) and via delivery by AAV expression vector (Grosse et al., Molecular Therapy 19(4):694-702 (2011), IDS ref., at pg. 694, last para., to pg., 695, 1st para.). Grosse teaches HSV-1-specific meganucleases (HSV1m1, HSV1m2, HSV1m4, and HSVm12) that inhibit/partially prevent HSV-1 infection of cells via blocking viral replication and reducing viral loads (at Fig. 1-6) and using such to prevent in vivo HSV1 reactivation in trigeminal nerves (i.e., clinical herpetic relapse) near the eye and/or lips (pg. 694, 699, last para., to pg. 700, para. 4). Grosse warns that challenges include achieving efficient enough delivery systems while avoiding in vivo toxicities and genetic damage (id.). More pertinently, the prior art teaches inactivating latent HSV infection in an infected cell using a meganuclease (HSV1m5) to introduce DSB in an HSV genome(s) within the HSV essential gene UL19 by delivering and expressing the meganuclease in the cell using an AAV vector (Aubert et al., Gene Therapy 21(3):e146 (2014), IDS ref.; Aubert et al., JCI Insight 1(14):e88468 (2016), IDS ref.).
Eliminating Completely
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In the claims, the term “eliminating” requires complete prevention of any detectable HSV-1 reactivation in the cell, as defined by the instant specification ([0086]). Although the instant specification shows working embodiments whereby latent HSV-1 is reduced by over 90% in a neuronal cell type ([0040], [0089], e.g., 92-95% in SCG at Example 1, Table 6), nowhere does the instant application describe complete prevention of any detectable HSV-1 reactivation in any cell. Further, as noted above while the art describes reducing HSV-1 reactivation, the prior art is silent as to any method accomplishing completely eliminating HSV-1 reactivation.
Effective Amount
Claim 1 purports to be for either reducing or eliminating latent HSV-1 reaction in a cell which presumably requires different effective amounts or at least some distinguishing feature to achieve one versus the other. As the instant claims fail to recite any distinguishing feature nor limit the amount of the viral vector(s) and/or HSV-1-specific meganuclease(s) delivered to the infected cell for these different results and the instant specification fails to describe any effective amount for eliminating, there is a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 1-27 as the specification fails to provide an effective amount to administer for predictably achieving the “eliminating.”
Additionally regarding claims 25-27, specifically recited effects are recited for the method of claim 19 without limitation as to the amount of the viral vector(s) and/or HSV-1-specific meganuclease(s) delivered as well as without limit to the amount of BET protein inhibitor administered. As there is also a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 25-27 as the claims fail to require an effective amount for predictably achieving each recited effect.
Regarding claim 23, the method is limited to wherein the dose of BET protein inhibitor does not exceed 3 µM to the HSV-1-infected cell; however, to accomplish this in a subject (as in claim 13 or 14), one needs to know which HSV-1 infected cell in the subject is the one(s) having the reduction or elimination and tailor the administration/dosage to avoid exceeding this ceiling. Similarly, to achieve specifically recited effects of claims 25-27 respectively, the minimum dosage must be kept above in theoretical floor for said cell(s). As the written description fails to describe how to achieve such over the scope of any BET protein inhibitor, any administering, any subject, and any infected cell type; thus, there is a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 23 and 25-27.
Viral Vector(s)
Claims 1, 6-9, 13-15, 19, and 23-27 encompass any viral vector(s) for delivering the encoding sequence to the infected cell under the ordinary and customary meaning of the term. The instant specification only describes viral vectors that are adeno-associated virus (AAV) while the prior art describes various types beyond AAV (e.g., lentivirus) as well as chimeric/mosaic hybrid AAVs. Thus, the genus of the term “viral vector” encompassed by claim 1 is broad while the description is narrow, limited to any AAV vector known in the art, e.g., AAV1-12, Rh8, and Rh10, and any engineered derivative thereof (see instant [0054]-[0055]). Also, if a plurality of viral vectors are used in the claimed method, then each may be of a different virus species or type, yet nowhere does the instant application describe anything other than using multiple serotypes of AAV together.
The described species lacks a sufficient nexus to the breadth of the genus of any viral vector and achieving reducing or preventing latent HSV-1 reactivation in any infected cell, such as within a subject. The described species also lacks a sufficient nexus to the breadth of an undetermined dosage that would be effective as recited at reducing or eliminating HSV-1 reactivation in a subject, such as achieving any result in a specific, infected cell type therein, e.g., a superior cervical ganglia (SCG) or trigeminal ganglia (TC) cell, as in claims 25-27. Note, the prior art teaches the packaging limit of an AAV is at most ~ 4.8 kb, which would be more inefficient than at 4.68 kb. while for scAVV the limit is about 2 kb (Choi et al., Curr Protoc Mol Biol, Ch. 16, Unit 16.25 (2007) at pg. 22, right col., Plasmid construction).
Delivering encoding sequence without expression or induction of targeted cut
Claim 1 purports to be for either reducing or eliminating latent HSV-1 reaction in a cell which in view of the prior art and instant description presumably requires both the expression of the meganuclease(s) in the receiving infected cell and a biological activity of said meganuclease(s) within the cell, i.e., an HSV-1-specific action. However none of claims 1-5 and 7-27 expressly requires either of these. To the contrary, in view of dependent claim 6, all the other present claims encompass whereby the meganuclease(s) do not induce any DNA DSB, such as in an HSV-1-specific target DNA sequence. Furthermore, in view of claim 7, claims 1-6 and 8-27 encompass wherein the target is outside an HSV-1 gene essential for replication. While the prior art teaches engineered meganucleases lacking catalytic activity, such as due to a substitution (Q47E) in recombinant I-CreI meganucleases (US20180289741A1 at [0354], [0007]-[0009]), the instant specification lacks any working example of reducing or eliminating latent HSV-1 reactivation in a cell using a catalytically inactive meganuclease.
Additionally, to achieve meganuclease(s) expression certain structures are required such as a promoter and perhaps a 3’ UTR. The written description fails to describe any delivering of a meganuclease activity to a cell for reducing latent HSV-1 reactivation without including a promoter operably linked to the meganuclease(s) encoding sequence(s). As the prior art is also silent to such transgene lacking promoters and 3’ UTR and this is merely prophetically claimed, there is lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 1-27 to predictably achieve any effect or biological result regarding HSV-1 infection merely by adding a meganuclease(s) encoding sequence. Thus, there is also necessarily a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 1-27 wherein there is not any regulatory element operably linked to the encoding sequence in the viral vector.
Regarding dependent claims 10-11, the instant description is silent as to any working embodiment of an scAAV vector comprising two or more meganuclease encoding sequences and capable of expressing such in an HSV-1-infected cell upon delivery. As the prior art is also silent to this meaning it instantly described merely prophetically, there is lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 10-11, such as comprising sequences encoding 3, 4, 5 or more HSV-1-specific meganucleases (e.g., co-expressed by dual-promoter or fused using an IRES or 2A sequence). Thus, there is also necessarily a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 1-27 wherein there are a plurality of meganuclease encoding sequences and the viral vector is an scAAV.
The specification fails to provide any viral vector or combination of viral vectors that completely prevents HSV-1 reactivation in a cell with reasonably predictability, such as in a superior cervical ganglia (SCG) or trigeminal ganglia (TC) cell. Thus, the specification also fails to provide an effective amount to administer for predictably achieving the aforementioned. Furthermore, the delivering of the HSV-1-specific meganuclease(s) is only described functionally while the working embodiments all rely on expression via a ubiquitous promoter, such as CMV or CBA promoter.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, or any combination thereof. Here, any viral vector and any meganuclease each encompasses a broad genus, without guidance as to which of these, or which features/characteristics of these, reasonably and predictably result in reductions in HSV-1 reactivation. Thus, the skilled artisan cannot envision which, or even how to identify which, viral vectors and meganucleases encoded by the aforementioned satisfy the claim limitation of reducing or eliminating HSV-1 reactivation in a cell. Therefore, there is a lack of evidence in the instant specification as filed that the inventors were in possession of the entire scope of claims 1-27.
HSV-1-specific Meganuclease(s)
Various types of meganucleases were known in the prior art, including of the AGLIDADG, GIY-YIG, His-Cys box, and HNH families (Castro et al. (2021) at pg. 2). The instant specification describes several examples of LAGLIDADG family members, such as I-Dmo I, PI-Sce I, PI-Pfu I, I-Cre I, I-Ppo I, I-Ceu I and a hybrid homing endonuclease I-Dmo I/I-Cre I called E-Dre I ([0046]-[0048]).
The term “HSV-1-specific” meganuclease or meganuclease “target sequence” is described broadly as encompassing any polynucleotide having 12 or more nucleotides, such as 12-60 nucleotides present anywhere in any HSV-1 genomic sequence, whether synthetic or naturally occurring, as well as an implied cleavage site related to said target (see Aubert et al. (2014) scAAV2-GFP at pg. 9, right col., 2nd para.; Grosse et al. (2011) recombinant HSV1 (rHSV1) at Fig. 2; Galetto et al., Expert Opin Biol Ther 9(10): 1289 (2009) at Fig. 3). Therefore, the target of just one meganuclease genus of claim 1 potentially encompasses over 20,000 to 1 x 1036 structural sequence variants (12^4 – 60^4) (www.calculator.net/exponent-calculator).
As there is no established correlation between all meganucleases, whether engineered or not, and all possible HSV-1 genomic sequences wherein the genome has been engineered, e.g., to encompass randomized sequences, the instant specification in view of the prior art fails to provide any additional species beyond the instant representative species disclosed. However Applicant is invited to provide evidence to the contrary.
Amgen, Inc., v. Sanofi (2023)
“Amgen seeks to monopolize an entire class of things defined by their function”. “The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a ‘vast’ number of additional antibodies that it has not.” “It freely admits that it seeks to claim for itself an entire universe of antibodies.” In the instant case, the claims encompass an enormously vast genus of meganucleases defined only functionally by having a cognate target sequence(s) present anywhere in any HSV-1 genome, as well as any polynucleotide capable of encoding the aforementioned packaged within a viral vector. However the only species described structurally in detail consist of SEQ ID NO: 1, 2, or 3; and the only working embodiments rely on the aforementioned.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the enormously vast genus of undisclosed polynucleotides encoding the vast number of undisclosed meganucleases defined only functionally as being HSV-1 specific. Thus, for the reasons outlined above and in view of Amgen, it is concluded that claims 1-7 and 9-27 do not meet the requirements for written description under 35 U.S.C. 112. All the aforementioned dependent claims fail to correct the primary deficiencies of claim 1.
The skilled artisan could not rely upon the disclosure such that the instant specification would sufficiently describe that Applicant was in possession of a method having a predictable effect for reducing or completely eliminating latent HSV-1 reactivation over the entire scope of the claims. While there is evidence that expressing one or more meganucleases targeting an essential gene in HSV-1 for DSB cleavage reduces HSV-1 reactivation after successful intracellular deliver of encoding polynucleotide, there is a lack of evidence in the prior art and instant application that the method of any of claims 1-27 achieves reduction of HSV-1 reactivation across the full scope of any claim as explained above.
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 2, 3-5, 10-12, 16-18, 20-22, and 25-27 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.
The claims are interpreted as set forth in a previous section.
In claim 2, the term viral vector expressly encompasses a viral vector that is both an scAAV and an ssAAV; however as these terms are mutually exclusive as interpreted herein based on ordinary and customary meanings as a self-complementary adeno-associated virus (scAAV) is a type of AAV virus having a partial dsDNA genome due to a terminal hairpin while a single-stranded adeno-associated virus (ssAAV) is type of AAV virus that can be defined by not being an scAAV (see [0111]; McCarty, Mol Ther 16: 1648-56 (2008) at pg. 1649, Fig. 1). Alternatively, all scAAV can be considered subtypes of AAV derived or engineered from an ssAAV format, which makes the use of “or” in claim 2 incoherent. If the applicant acts as her own lexicographer to redefine a term of a claim contrary to its ordinary meaning, the written description must clearly define the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). In the instant case, there is no such clear redefinition of “scAAV” and/or “ssAAV.” Thus, claim 2 is indefinite because the distinction between the terms “scAAV” and “ssAAV” are incoherent and unclear. Claims 3-5, 10-12, 16-18, and 20-22 are included in this rejection for depending from an indefinite claim.
Claims 4-5, 11-12, 16-18, and 20-22 each recites “scAAVs,” which and lacks clear antecedent basis. Note, the instant specification defines words “using the singular or plural number also include the plural and singular number, respectively” (pg. 30, 5th para. [0080]).
Claim 16 recites the phrase “configured for injection” regarding a pharmaceutically acceptable carrier, which as noted above is interpreted pursuant to 35 U.S.C. 112(f) to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The instant specification is silent as to any corresponding structure and, thus, this phrase is indefinite. Claims 17-18 are included in this rejection for depending from indefinite claim 16.
Claim 16-18 and 20-22 recites “the one or more scAAVs,” which lacks sufficient antecedent basis within in the claim or in a claim from which it depends.
Claims 25 and 26 each recites the “SCG cell,” which lacks sufficient antecedent basis in the claim or any claim from which it depends.
Claim 27 recites the “TG cell,” which lacks sufficient antecedent basis in the claim or a claim from which it depends.
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 3, 6, and 25-27 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.
The claims are interpreted as set forth in a previous section.
Claim 3 attempts to narrow the scAAV and/or ssAAV of claim 2 to “scAAV,” however this fails to further limit any element of claim 2 (see 112(b) rejection above).
Claim 6 recites wherein the one or more meganucleases is configured to induce one or more DNA double-stranded breaks (DSB). However, the term “HSV-1 specific meganuclease” ordinary and customary meaning implies the presence of an inherent capability to induce a DSB, e.g., within a DNA molecule substrate having an HSV-1 associated sequence. Thus, claim 6 fails to further limit the term “HSV-1 specific meganuclease” in claim 1. To the extent applicant wants to argue to the contrary, note “configured to induce one or more double-stranded breaks” is interpreted pursuant to 35 U.S.C. 112(f) to cover only the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
Claims 25-27 each attempts to narrow the scope of claim 19 to wherein said delivering and administering produces a specifically recited effect; however, each of these effects either inherently occurs by performing the method of claim 19 or each of claims 25-27 lacks sufficient written description of the claimed method (see 112(a) section above).
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 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 1-9, 13, and 15-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aubert (Aubert et al., JCI Insight 1: e88468 (2016), IDS ref.).
The claims are interpreted as set forth in a previous section.
Regarding claim 1, Aubert discloses a method of delivering to HSV-1 latently infected cells an AAV viral vector expressing a catalytically active meganuclease (HSV1m5 or HSV1m8) targeting an HSV-1 sequence for endonucleolytic cleavage to prevent HSV-1 reactivation in the cell, such as within a mammalian subject (abstract, pg. 4-8, Fig. 2-5, 7; Tables 3-4). Further, Aubert discloses such methods according to the aforementioned for reducing latent HSV-1 reactivation in neuronal cells in a mammalian subject, e.g., 1-4% of cells in aggregate (id.).
Regarding claims 2-5, Aubert discloses wherein the viral vector is an scAAV virus having a serotype of AAV1 or AAV8 (pg. 13, pg. 2; Fig. 3B).
Regarding claims 6-7, Aubert discloses wherein the meganuclease causes DSB in HSV genomic DNA (e.g., episomal), and this HSV-1-specific meganuclease targets an essential gene for HSV-1 replication (UL19 or UL30) (Fig. 1A-B).
Regarding claim 8, although Aubert does not disclose any sequence for the meganucleases, HSV1m5 inherently consists of HSV1m5 inherently consists of SEQ ID NO: 1 and targets SEQ ID NO: 4 while HSV1m8 inherently consists of SEQ ID NO: 2 and targets SEQ ID NO: 6 in view of instant [0091], [0060]-[0061].
Regarding claim 9, Aubert discloses wherein the target sequence is SEQ ID NO: 4 or 6 (Fig. 1B).
Regarding claim 13, Aubert discloses wherein the subject is a mammal (mouse) (Fig. 7).
Regarding claim 15, Aubert disclose wherein the cell is a trigeminal ganglion (TG) neuron (pg. 2).
Regarding claims 16-18, Aubert discloses wherein the viral vector (AAV virus) is in a composition comprising a pharmaceutically acceptable carrier for injection as evidenced by successful subcutaneous/intramuscular "whiskerpad" injection into mice and reduction of latent HSV-1 (pg. 6-7, Fig. 7).
Regarding claims 19-24, although Aubert does not disclose the method comprises administering a BET protein inhibitor, as indicated by dependent claim 23, the scope of claim 19 encompasses any dose of BET protein inhibitor with no minimum (e.g., a de minimis dose), and thus, the method disclosed by Aubert anticipates claims 19-24 for BET protein inhibitor concentrations having no functional consequence on the claimed method in the absence of evidence that even a miniscule amount of BET protein inhibitor can do such (e.g., a quectogram/mL, rentogram/mL, or any subpicomolar dose).
Thus, Aubert anticipates the claimed invention.
Claims 1-7 and 11-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aubert2 (Aubert et al., Nat Commun. 11: 4148 (Aug. 18, 2020); IDS ref.).
Regarding claim 1, Aubert2 discloses a method of delivering to HSV-1 latently infected cells a viral vector (AAV) expressing a catalytically active meganuclease (HSV1m5, HSV1m8, and/or HSV1m4) targeting an HSV-1 sequence for endonucleolytic cleavage to prevent HSV-1 reactivation in the cell (abstract, pg. 2, left col., last para.; pg. 13, right col.). Further, Aubert2 discloses such methods according to the aforementioned for reducing latent HSV-1 reactivation in a neuronal cell in a mammalian subject, e.g., by as much as 94.6% (id.; Table 1-2).
Regarding claims 2-5, Aubert2 discloses wherein the viral vector is an scAAV virus (pg. 2, 2nd para.; pg. 13, right col., 2nd para.), such as having a serotype of AAV1, AAV8, or Rh10 as well as the combinations (e.g., AAV1+8, AAV1+Rh10, AAV8+10 or all three) (Fig. 1-4, 8, pg. 11, left col.; Table 2).
Regarding claim 6, Aubert2 discloses wherein the meganuclease causes DSB in HSV genomic DNA (pg. 2, right col.; Fig. 1-2).
Regarding claim 7, Aubert2 discloses wherein the HSV-1-specific meganuclease targets an essential gene for HSV-1 replication (UL30 or UL19) (pg. 2, left col., 3rd para.).
Regarding claims 11-12, Aubert2 discloses the method comprising two different scAAV to deliver two different HSV-1-specific meganucleases concomitantly (“dual-meganuclease therapy”), i.e., wherein the sequences are different (e.g., HSV1m5 and HSV1m8) (pg. 2, right col., para. 5; Fig. 3-4; Table 2).
Regarding claim 13, Aubert2 discloses wherein the subject is a mammal (mouse) (pg. 13, right col., Fig. 1-4 and 8, Tables 1-2).
Regarding claim 14, Aubert2 discloses wherein the subject is a human (abstract).
Regarding claim 15, Aubert2 disclose wherein the cell is an superior cervical ganglion (SCG) or trigeminal ganglion (TG) (Fig. Fig. 1-4, 8, Tables 1-2; pg. 2, left col., last para.).
Regarding claim 16, Aubert2 discloses wherein the viral vector (AAV virus) is in a composition comprising a pharmaceutically acceptable carrier for injection as evidenced by successful injection into mice and reduction of latent HSV-1 reactivation (pg. 13, right col.).
Regarding claim 17, Aubert2 discloses wherein delivery comprises subcutaneous injection of a carrier composition comprising one or more of the scAAV (whisker pad injection) (pg. 13, right col., para. 4).
Regarding claim 18, Aubert2 discloses wherein delivery comprises intramuscular injection of a carrier composition comprising one or more of the scAAV (whisker pad injection) (pg. 13, right col., para. 4).
Regarding claims 19-24, although Aubert2 does not disclose the method comprises administering a BET protein inhibitor, as indicated by dependent claim 23, the scope of claim 19 encompasses any dose of BET protein inhibitor with no minimum (e.g., a de minimis dose), and thus, the method disclosed by Aubert2 anticipates claims 19-24 for BET protein inhibitor concentrations having no functional consequence on the claimed method in the absence of evidence that even a miniscule amount of BET protein inhibitor can do such (e.g., a quectogram/mL, rentogram/mL, or any subpicomolar dose).
Thus, Aubert2 anticipates the claimed invention.
Claim Rejections - 35 USC § 103
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.
Claims 1-24 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert (Aubert et al., JCI Insight 1: e88468 (2016), IDS ref.) in view of Balazs (US 20120232133 A1, IDS ref.).
As set forth fully above, claims 1-9, 13, and 15-24 are anticipated by Aubert and, thus, the subject matter of claims 1-9, 13, and 15-24 is obvious over Aubert.
Regarding claim 10, Aubert does not teach an scAAV vector comprising a genomic DNA encoding two or more meganucleases.
However Aubert teaches a method of reducing latent HSV-1 reactivation in mammalian cells by administering two scAAV viral vectors, one expressing a meganuclease targeting an HSV-1 gene essential for replication for DSB DNA cleavage (HSV1m5 or HSV1m8) and the other expressing Trex2. Note for purposes of applying prior art, an intended result only limits the claim if there is an implied feature or step not recited in the claims. See MPEP 2111.02. Furthermore, Balazs teaches recombinant scAAV vectors for expressing one or more proteins of interest in a host cell ([0138], [0008], [0040]-[0041]; [0067]; [0082]-[0084]; [0092]; [0103]; [1041]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to engineer two meganuclease (e.g., HSV1m5 and HSV1m8) encoding sequences taught by Aubert as proteins of interest into a single scAAV vector as taught by Balazs for use in a method of Aubert. One of ordinary skill in the art would be motivated to create multiple DNA DSBs to better ensure HSV-1 inactivation.
Regarding claims 11-12, Aubert does not teach delivering two scAAV vector, each comprising a sequence encoding a different HSV-1-specific meganuclease. However it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to deliver both scAAV vectors disclosed in Aubert (encoding HSV1m5 and HSV1m8) for use in a method of Aubert. One of ordinary skill in the art would be motivated to create multiple DNA DSBs to better ensure HSV-1 inactivation.
Regarding claim 14, Aubert teaches a clinical therapeutic approach of delivering to HSV-1 latently infected cells in a subject an AAV viral vector expressing a DSB creating meganuclease (the anti-HSV CreI first generation derivatives HSV1m5 or HSV1m8) targeting an HSV-1 sequence for cleavage (SEQ ID NO: 4 or 6) to prevent HSV-1 reactivation in such infected cells (pg. 12-13; abstract, pg. 4-8, Fig. 2-5, 7; Tables 3-4). Aubert shows some success in a mouse model, including regarding safety profiles (toxicity risks, inflammation and off-target damage) (id.). Aubert stresses that because HSV latent genomes are restricted to a small number of neurons of sensory and autonomic ganglia, there is a reasonable expectation of success, at least compared to targeting other common persistent viral infections of humans.
Claims 1-9, 13, 15-22, and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert (Aubert et al., JCI Insight 1: e88468 (2016)) in view of Groves (Groves et al., Front Cell Infect Microbiol 10: 329 (Jul. 2, 2020); IDS ref.).
As set forth fully above, claims 1-9, 13, and 15-18 are anticipated by Aubert and, thus, the subject matter of claims 1-9, 13, and 15-18 is obvious over Aubert. The claims are interpreted as set forth in a previous section.
Regarding claims 19-22, Aubert does not teach the method comprises also administering to the infected cell an effective amount of a bromodomain and extra-terminal (BET) protein inhibitor.
However Groves teaches administering an HSV-1 infected cell a sufficient amount of a BET protein inhibitor (BET bromodomain inhibitor or BRDi) to act as a latent-reversal agent (LRA) therapeutic to help purge a latent virus reservoir (pg. 4, left col., Table 1; pg. 6, left col.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine administering the scAAV virus(es) as taught by Aubert with administering a BRDi (BET protein inhibitor) as taught by Groves to reduce or eliminate latent HSV-1 reactivation in a cell or subject, such as simultaneously or in either order. One of ordinary skill in the art would be motivated to use two therapeutic approaches in combination to better reduce/eliminate HSV-1, especially to use the BRDi as a latency reversal agent, as taught by Groves, for targeting activated HSV-1 virus with meganuclease destruction. Further, It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine the scAAV and BRDi in any order as there is only limited choices possible (i.e., before, after, or together) but all with a reasonable expectation of success as explained below regarding claim 26.
Regarding claim 24, Groves teaches wherein the BET protein inhibitor (BRDi) is JQ1 (pg. 5, 1st para.).
Regarding claim 26, Aubert teaches wherein delivering one scAAV virus alone encoding one anti-HSV CreI first generation derivative mutates latent HSV1 genomes and inhibits production of new virus from latently infected cells (pg. 10).
Regarding claims 25-27, even if Aubert in view of Groves does not expressly teach wherein the delivering and administering produces the specifically recited effects, because this prior art combination teaches the same positively recited method steps, then these claimed effects are considered based on the logic of the claim as drafted and in the absence of evidence to the contrary to be inherent outcomes of performing the process as positively recited by the natural laws of biology. To the extent any of these effects are argued to be absent from the method taught by the prior art laid out above, note the 112(a) rejection above.
Claims 1-9, 13, 15-18, and 23-27 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert in view of Groves as applied above, and further in view of Alfonso-Dunn (Alfonso-Dunn et al., Cell Host Microbe 21: 507-17 (2017); IDS ref.) and Daboussi (Daboussi et al., Nucleic Acids Res 40: 6367-79 (2012)).
Regarding claim 23, the combination of Aubert and Groves does not teach using any specific BET protein inhibitor concentration.
However Daboussi teaches meganuclease (MN) DNA DSB cleavage efficacy depends on the chromatin state, with transcriptionally “open” chromatin state of gene showing higher efficacy than “closed” chromatin states, and concluding that “target accessibility” is a major determinant of efficacy of engineered homing endonucleases (pg. 6375, last para., to pg. 6377; Fig. 3-5).
Further, Alfonso-Dunn teaches using BET protein inhibitor concentrations of 3 µM or less (e.g., of JQ1, iBET762, or HMBA) can induce reactivation of latent HSV-1 in an infected cell while inhibiting HSV immediate early gene expression (E5, 3rd para. pg. 511-512, Fig. 6-7). In particular, Alfonso-Dunn teaches BET protein inhibitors which bind to the bromodomains of BRD4 (“BRD4-BET Inhibitors”) inhibit its binding to chromatin involved in HSV1 reactivation gene expression chromatin opening during the switch from latent to lytic, with empirical data shown for JQ1 at concentrations 0.5 or 1 µM (pg. 511-512; Fig. 6-7, 3D).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine administering the scAAV virus as taught by Aubert with administering a BET protein inhibitor with BRD4 inhibition at a concentration no greater than 3 µM (e.g., JQ1 at 0.5-1 µM) as taught by Alfonso-Dunn to induce latent HSV chromatin opening (initial stage of reactivation) into an open chromatin configuration. One of ordinary skill in the art would be motivated by Daboussi teaching meganuclease activity is sensitive to chromatin state, where the closed configuration of latent HSV1 genome should be more inaccessible than an open configuration induced/enhanced by a BET protein inhibitor, especially when developing in vivo uses in a subject. Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective time of filing in the absence of evidence to the contrary.
Claims 1-9 and 11-24 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert2 (Aubert et al., Nat Commun. 11: 4148 (Aug. 18, 2020); IDS ref.) in view of Choulika (US 20120171191 A1).
As set forth fully above, claims 1-7 and 11-24 are anticipated by Aubert2 and, thus, the subject matter of claims 1-7 and 11-24 are obvious over Aubert2. The claims are interpreted as set forth in a previous section.
Regarding claims 8-9, Aubert2 does not expressly teach any sequence comprised by the one or more meganucleases nor any specific target sequence, which depends on said meganuclease protein sequence.
However Aubert2 teaches a method of reducing latent HSV-1 reactivation in mammalian cells by administering one or more scAAV viral vectors, each expressing a meganuclease targeting an HSV-1 gene for DSB cleavage, e.g., UL30, UL19 or ICP0 (Abstract - "curative approach to treat latent HSV infection. Here we show that AAV-delivered meganucleases, but not CRISPR/Cas9, mediate highly efficient gene editing of HSV,” eliminating over 90% of latent HSV-1 virus (abstract, pg. 2, left col.; pg. 13, right col., Tables 1-2). Note for purposes of applying prior art, an intended result only limits the claim if there is an implied feature or step not recited in the claims. See MPEP 2111.02. Here, the intended result of “reducing or eliminating latent” HSV-1 reactivation in an HSV-1-infected cell (whether in vitro or in vivo) is either an inherent result of the active steps of claim 1 as indicated by logic of the claim as drafted or claim 1 is deficient in providing an essential step or feature to ensure such results (see 112(a) rejection above).
Regarding claim 8, Choulika teaches an engineered meganuclease (a recombinant LAGLIDADG heterodimer) comprising instant SEQ ID NO: 1 (SEQ ID NO: 454 or 534) as shown below, and for genome editing of an HSV-1-infected cell or cleaving HSV-1 genomic DNA to inhibit an HSV-1 virus or prevent infection (Examples 2 and 8, FIG. 36, 41-44, 48, 53; Table XXXIII; abstract; [0116]-[0117]).
Query Match 100.0%; Score 1790; Length 354;
Best Local Similarity 100.0%;
Matches 352; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 NTKYNEEFLLYLAGFVDGDGSIIAQIKPNQSYKFKHQLSLTFMVTQKTQRRWFLDKLVDE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3 NTKYNEEFLLYLAGFVDGDGSIIAQIKPNQSYKFKHQLSLTFMVTQKTQRRWFLDKLVDE 62
Qy 61 IGVGYVRDAGSVSNYILSKIKPLHNFLTQLQPFLELKQKQANLALKIIEQLPSAKESPDK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 63 IGVGYVRDAGSVSNYILSKIKPLHNFLTQLQPFLELKQKQANLALKIIEQLPSAKESPDK 122
Qy 121 FLEVCTWVDQVAALNDSKTRKTTSKTVRAVLDSLGEKKKSSPAAGGSDKYNQALSKYNQA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 123 FLEVCTWVDQVAALNDSKTRKTTSKTVRAVLDSLGEKKKSSPAAGGSDKYNQALSKYNQA 182
Qy 181 LSKYNQALSGGGGSNKKFLLYLAGFVDSDGSIIAQIKPNQEYKFKHYLSLTFAVTQKTQR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 183 LSKYNQALSGGGGSNKKFLLYLAGFVDSDGSIIAQIKPNQEYKFKHYLSLTFAVTQKTQR 242
Qy 241 RWFLDKLVDRIGVGYVYDSGSVSYYKLSKIKPLHNFLTQLQPFLKLKQKQANLALKIIEQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 243 RWFLDKLVDRIGVGYVYDSGSVSYYKLSKIKPLHNFLTQLQPFLKLKQKQANLALKIIEQ 302
Qy 301 LPSAKESPDKFLEVCTWVDQVAALNDSKTRKTTSETVRAVLDSLSEKKKSSP 352
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 303 LPSAKESPDKFLEVCTWVDQVAALNDSKTRKTTSETVRAVLDSLSEKKKSSP 354
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to choose any HSV-1-specific meganuclease known in the prior art for use in a method of Aubert2 with a reasonable expectation of success. One of ordinary skill in the art would be motivated to use a recombinant LAGLIDADG heterodimer meganuclease taught by Choulika as already validated to cleave within an HSV-1 gene (e.g., UL30, UL19 or ICP0 as taught by Aubert2 at pg. 2 left col., 3rd para.) for a predictable prior art purpose when Choulika teaches meganucleases comprising SEQ ID NO: 1 exhibited genome editing of an ICP0 sequence (FIG. 41, 31-39%), up to 46% HSV1 virus inhibition (FIG. 44, 48), and 51-87% inhibition of HSV1 replication (FIG. 53).
Regarding claim 9, Aubert2 does not expressly teach any specific target sequence of the meganuclease(s). However Choulika teaches using engineered meganucleases to target and cleave instant SEQ ID NO: 4 (SEQ ID NO: 24), as shown below, for DSB cleavage within the UL19 gene (Example 1, [0122], FIG. 3).
Query Match 100.0%; Score 24; Length 24;
Qy 1 ATAAACTCACACACGGCGTCCTGG 24
||||||||||||||||||||||||
Db 1 ATAAACTCACACACGGCGTCCTGG 24
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to choose any essential HSV-1 gene taught by Aubert2 to reduce the HSV-1 reactivation capability in the cell with a reasonable expectation of success. One of ordinary skill in the art would be motivated to target the UL19 gene as taught by Aubert2 using a meganuclease already validated to successfully cleave UL19 by specifically cleaving an HSV-1 virus genomic sequence as taught by Choulika (FIG. 1).
Claims 1-7 and 10-24 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert2 (Aubert et al., Nat Commun. 11: 4148 (Aug. 18, 2020)) in view of Balazs (US 20120232133 A1).
As set forth fully above, claims 1-7 and 11-24 are anticipated by Aubert2 and, thus, the subject matter of claims 1-7 and 11-24 is obvious over Aubert2.
Regarding claim 10, Aubert2 does not teach an scAAV vector comprising a genomic DNA encoding two or more meganucleases. However Aubert2 teaches a method of reducing latent HSV-1 reactivation in mammalian cells by administering two scAAV viral vectors, each expressing a different meganuclease targeting a different HSV-1 gene for DSB DNA cleavage (HSV1m5, HSV1m8, and/or HSV1m4) (abstract, pg. 2, left col.; pg. 13, right col., Tables 1-2). Note for purposes of applying prior art, an intended result only limits the claim if there is an implied feature or step not recited in the claims. See MPEP 2111.02.
Furthermore, Balazs teaches recombinant scAAV vectors for expressing one or more proteins of interest in a host cell ([0138], [0008], [0040]-[0041]; [0067]; [0082]-[0084]; [0092]; [0103]; [1041]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to engineer two meganuclease encoding sequences taught by Aubert2 as proteins of interest (e.g., HSV1m5 and HSV1m8) into a single scAAV vector as taught by Balazs for use in a method of Aubert2. One of ordinary skill in the art would be motivated by Aubert2 teaching that combining expression of two different meganucleases (e.g., HSV1m5 and HSV1m8 (“m5+m8”) or HSV1m5 and HSV1m4 (“m5+m4”)) in the same cell was more effective than using either separately (Fig. 1-4, Table 1.
Claims 1-7, 11-22, and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert2 (Aubert et al., Nat Commun. 11: 4148 (Aug. 18, 2020)) in view of Groves (Groves et al., Front Cell Infect Microbiol 10: 329 (Jul. 2, 2020)).
As set forth fully above, claims 1-7 and 11-18 are anticipated by Aubert2 and, thus, the subject matter of claims 1-7 and 11-18 is obvious over Aubert2. The claims are interpreted as set forth in a previous section.
Regarding claims 19-22, Aubert2 does not teach the method comprises also administering to the infected cell an effective amount of a bromodomain and extra-terminal (BET) protein inhibitor.
However Groves teaches administering an HSV-1 infected cell a sufficient amount of a BET protein inhibitor (BET bromodomain inhibitor or BRDi) to act as a latent-reversal agent (LRA) therapeutic to help purge a latent virus reservoir (pg. 4, left col., Table 1; pg. 6, left col.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine administering the scAAV virus(es) as taught by Aubert2 with administering a BRDi (BET protein inhibitor) as taught by Groves to reduce or eliminate latent HSV-1 reactivation in a cell or subject, such as simultaneously or in either order. One of ordinary skill in the art would be motivated to use two therapeutic approaches in combination to better reduce/eliminate HSV-1, especially to use the BRDi as a latency reversal agent, as taught by Groves, for targeting activated HSV-1 virus with meganuclease destruction. Further, It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine the scAAV and BRDi in any order as there is only limited choices possible (i.e., before, after, or together) but all with a reasonable expectation of success as explained below regarding claim 26.
Regarding claim 24, Groves teaches wherein the BET protein inhibitor (BRDi) is JQ1 (pg. 5, 1st para.).
Regarding claim 26, Aubert2 teaches wherein delivering the scAAV viruses alone reduces HSV-1 load at least 83% in SCG cells (> 90%) at least 48 hours later (2 weeks after or at least 30 days later: Fig. 2, 86%; Fig. 90% or 95%; Fig. 8, 92%; Tables 1-2).
Regarding claims 25-27, even if Aubert2 in view of Groves does not expressly teach wherein the delivering and administering produces the specifically recited effects, because this prior art combination teaches the same positively recited method steps, then these claimed effects are considered based on the logic of the claim as drafted and in the absence of evidence to the contrary to be inherent outcomes of performing the process as positively recited by the natural laws of biology. To the extent any of these effects are argued to be absent from the method taught by the prior art laid out above, note the 112(a) rejection above.
Claims 1-7 and 11-27 are rejected under 35 U.S.C. 103 as being unpatentable over Aubert2 in view of Groves as applied above, and further in view of Alfonso-Dunn (Alfonso-Dunn et al., Cell Host Microbe 21: 507-17 (2017); IDS ref.) and Daboussi (Daboussi et al., Nucleic Acids Res 40: 6367-79 (2012)).
Regarding claim 23, the combination of Aubert2 and Groves does not teach using any specific BET protein inhibitor concentration.
However Daboussi teaches meganuclease (MN) DNA DSB cleavage efficacy depends on the chromatin state, with transcriptionally “open” chromatin state of gene showing higher efficacy than “closed” chromatin states, and concluding that “target accessibility” is a major determinant of efficacy of engineered homing endonucleases (pg. 6375, last para., to pg. 6377; Fig. 3-5).
Further, Alfonso-Dunn teaches using BET protein inhibitor concentrations of 3 µM or less (e.g., of JQ1, iBET762, or HMBA) can induce reactivation of latent HSV-1 in an infected cell while inhibiting HSV immediate early gene expression (E5, 3rd para. pg. 511-512, Fig. 6-7). In particular, Alfonso-Dunn teaches BET protein inhibitors which bind to the bromodomains of BRD4 (“BRD4-BET Inhibitors”) inhibit its binding to chromatin involved in HSV1 reactivation gene expression chromatin opening during the switch from latent to lytic, with empirical data shown for JQ1 at concentrations 0.5 or 1 µM (pg. 511-512; Fig. 6-7, 3D).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine administering the scAAV virus(es) as taught by Aubert2 with administering a BET protein inhibitor with BRD4 inhibition at a concentration no greater than 3 µM (e.g., JQ1 at 0.5-1 µM) as taught by Alfonso-Dunn to induce latent HSV chromatin opening (initial stage of reactivation) into an open chromatin configuration. One of ordinary skill in the art would be motivated by Daboussi teaching meganuclease activity is sensitive to chromatin state, where the closed configuration of latent HSV1 genome should be more inaccessible than an open configuration induced/enhanced by a BET protein inhibitor, especially when developing in vivo uses in a subject. Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective time of filing in the absence of evidence to the contrary.
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).
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Claims 1-7 and 10-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 16, and 18-28 of copending Application No. 18/670,419 (reference application) as evidenced by Koelle (Koelle et al., Sci Rep 7 :44084 (2017)).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 18-19 of the reference application each teaches methods of reducing or eliminating latent Herpes simplex virus reactivation in an infected cell by administering one or more viral vectors encoding an Herpes simplex virus (HSV)-specific meganuclease. While instant claims 1 differs in that the Herpes simplex virus type is type 1 (HSV-1) while the reference claims are specific to type 2 (HSV-2), however the genomic sequences of HSV-1 and HSV-2 are so similar (e.g., 50-74% homologous) that an HSV-specific meganuclease as evidenced by Koelle can simultaneously have specificity for both HSV-2 and HSV-1. For example, Koelle teaches certain HSV-2 genomes contains multiple regions of over 200-400 bp that are identical to the HSV-1 genome, such as in the UL29, UL30 and UL39 genes (abstract, Table 2).
Instant claims 2-3 are taught by reference claim 2. Instant claims 4-5 are taught by reference claims 3-4 and 16. Instant claim 6 is taught by reference claims 6-8. Instant claim 7 is taught by reference claim 5 or 9. Instant claims 10-12 are taught by reference claim 16. Instant claims 13-14 are taught by reference claims 27-28. Instant claim 15 is taught by reference claim 22. Instant claim 16 is taught by reference claim 26. Instant claims 17-18 are taught by reference claims 25-26.
This is a provisional nonstatutory double patenting rejection because the reference application claims have not in fact been patented.
Claims 1-7, 10-22, and 24-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 16, and 18-28 of copending Application No. 18/670,419 (reference application) as evidenced by Koelle as applied above, and further in view of Groves.
Regarding instant claims 19-22, the reference claims do not teach wherein the method further comprises administering a BET protein inhibitor. However Groves teaches administering an HSV-1 infected cell a BET protein inhibitor (BET bromodomain inhibitor or BRDi), such as to act as a latent-reversal agent (LRA) therapeutic to help purge a latent virus reservoir (pg. 4, left col., Table 1; pg. 6, left col.). Thus, it would have been prima facie obvious to one of ordinary skill in the art to combine administering the viral vector(s) expressing an HSV-2-specific meganuclease that is also HSV-1 specific as taught above with administering a BET protein inhibitor (BRDi) as taught by Groves to reduce or eliminate latent HSV-1 reactivation in a cell or subject, such as simultaneously or in either order. One of ordinary skill in the art would be motivated to use two therapeutic approaches in combination to better reduce/eliminate HSVs, especially to use the BRDi as a latency reversal agent as taught by Groves. Further, It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to combine the administering of the viral vector(s) and BRDi in any order as there is only limited choices possible (i.e., before, after, or together).
Regarding instant claim 24, Groves teaches wherein the BET protein inhibitor (BRDi) is JQ1 (pg. 5, 1st para.). Regarding instant claims 25-27, even if the reference claims in view of Groves as evidenced by Koelle does not expressly teach wherein the delivering and administering produces the effects recited in claims 25-27, because a method comprising the same positively recited method steps is obvious then these claimed effects are considered to be inherent outcomes of performing the process as positively recited by the natural laws of biology. This is a provisional nonstatutory double patenting rejection because the reference application claims have not in fact been patented.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
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