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 .
Application Status
The action is written in response to applicant’s correspondence received on 12/02/2024. Claims 1-16, 20-21, 24, 27-28, 40, 42-45, and 47-49 are currently pending.
Priority
The instant application claims priority to US provisional application 63/270,189, with an effective filing date of 10/21/2021.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Currently, drawings submitted on 4/18/2024 as a supplemental file contains the colored versions of all figures submitted in black and white. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The use of the term TweenTM and PluronicsTM (see paragraph 0066), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 5, 13, 24, and 42 is objected to because of the following informalities:
Regarding claim 5, 13, and 24, applicant recites “nucleosides” followed by “nucleotides” within the same claim (claim 5) and all claims ultimately depend on claim 1. While these may be interchangeable in the art, the terminology should remain consistent throughout the claim.
Claim 42 recites “…Parkinson’s disease, or Amyotrophic Lateral Sclerosis, neuropathic pain…” which leads neuropathic paid with no conjunction. The statement should read “Parkinson’s disease, ALS, or neuropathic pain…”. Claim 42 also recites the genes NLRP3, RELA, RIPK1, or CD22, SCN9A, SCN10A, TRKA gene, wherein the placement of the “or” should be after SCN10A.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description
Claims 1-16, 20-21, 24, 27-28, 40, 42-45, and 47-49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The factors to be considered when analyzing claims for compliance with the written description requirement include: (A) actual reduction to practice; (B) disclosure of drawings or structural chemical formulas; (C) sufficient relevant identifying characteristics (e.g., complete structure, partial structure, physical and/or chemical properties, structure/function correlation); (D) level of skill and knowledge in the art; and (E) predictability in the art.
Each of the factors (A)-(E) listed above is analyzed below:
Actual Reduction to Practice
For the actual reduction to practice, applicant discloses Figs. 14B which describes the structure of CASi B: mir23-HTT T1 CASi. Fig. 17-20 discloses the administration of CASi complexes in mice and analyzes the levels of HTT mRNA expression.
Disclosure of Drawings or Structural Chemical Formulas
Applicant discloses 20 sequences in the sequence listing and Figs. 13 and 14 which shows two CASi constructs incorporating siRNA and miRNA targeting GFAP-HTT T2 and HTT T1, respectively.
Structure
Applicant discloses that the structure of the RNA complex comprises a guide strand, passenger strand, and sensor strand. In design 1, applicant discloses wherein the passenger strand is the core strand that binds with the sensor strand whereas in design 3, the guide strand forms the core strand and is bound to the sensor strand. Applicant discloses that upon release of an input strand to the sensor strand, the sensor strand is displaced, allowing for either a miRNA or siRNA duplex to bind to the target mRNA.
The Level of Skill in the Art
The level of skill in the art is high. A skilled artisan would require an understanding of conditional activatable RNA complexes as well as an understanding of RNAi.
Predictability in the Art
The art describes siRNA design as very well known, as evidenced by Zare et al. (Precise and efficient siRNA design: a key point in competent gene silencing, Cancer Gene Therapy, Volume 23, pgs. 73-82, published 3/18/2016), where in target site, location within the target sequence, and other factors are important for siRNA efficiency (see Basic criteria for designing siRNAs). However, as target site is an important part of siRNA design, an siRNA that targets a specific target sequence would not be applicable to a target mRNA of any sequence.
In view of the foregoing, the claims 1-16, 20-21, 24, 27-28, 40, 42-45, and 47-49 are rejected for failing to comply with the written description requirement as claim 1 broadly recites a method of modulating a target RNA, which can be ANY target RNA, in the nervous system of a subject and claim 2 recites a method of treating a neurological disorder, wherein the disorder can be ANY disorder. As applicant describes the use of siRNA and miRNA, applicant does not provide all the target sequences or inhibitory sequences necessary that would convince a skilled artisan that the inventors had possession of a construct that can modulate all nervous system mRNA, including genes and disorders except for Huntingtin’s disease. This is further evidenced by the reduction to practice, wherein applicant only show the reduction of HTT mRNA through miRNA and siRNA inhibition.
Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4, 6, 20, and 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.
Regarding claim 1, applicant recites a method of modulating “a target RNA in the nervous system of a subject” and later in the claim recites “the first nucleic acid duplex comprises a sequence complementary to a target RNA”. It is unclear if the target RNA that is being modulated is the same target RNA that the first duplex has a sequence complementary to.
Claim 1 also recites “the nervous system of a subject” without using proper antecedent basis of “a nervous system”. Claim 27 depends on claim 1 and further recites “the nervous system” comprises “a central nervous system”, indicating that antecedent basis is improper in claim 1.
Regarding claim 2, applicant recites “the first nucleic acid duplex comprises a sequence complementary to a target RNA” and then later recites “release the sequence complementary to a target RNA related to the neurological disease or disorder”. It is unclear if the target RNA where the sequence is complementary to for the reduction of expression is the same target RNA recited in the first duplex.
Regarding claim 4, applicant recites where the first strand bound to the second strand comprises “a sequence complementary to the target RNA”. Claim 4 depends on claim 1 which already recites “a sequence complementary to the target RNA”. It is unclear if the recited sequences are the same.
Regarding claims 4 and 6, applicant recites the term “the second nucleic acid”. The term “second nucleic acid” lacks antecedent basis as Claim 1 recites “a second nucleic acid strand”. It is unclear if the second nucleic acid refers to the second nucleic acid strand recited in claim 1.
Regarding claim 20, applicant recites where the binding of the input nucleic acid strand on the third nucleic acid strand causes the displacement of the second nucleic acid strand from the first nucleic acid strand. Claim 1, which claim 20 is dependent on, recites where the third nucleic acid strand binds an input nucleic acid to cause the displacement of the third nucleic acid strand from the first nucleic acid strand. It is unclear which strand is displaced (the third or second strand), as the second strand being displaced from the first and the third strand being displaced from the first can be viewed as contradictory outcomes.
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 8 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 8 recites where the central region of the first nucleic acid strand comprises the sequence complementary to the target RNA. Claim 8 depends on claim 7, which ultimately depends on claim 4, wherein claim 4 recites “the portion of the first nucleic acid strand that is bound to the second nucleic acid strand comprises a sequence complementary to the target RNA” and claim 7 recites wherein “the second nucleic acid strand binds to the central region of the first nucleic acid strand”. If claim 4 describes wherein the portion of the first strand that binds to the second strand comprises the complementary sequence, and claim 7 says the second strand binds to the central region of the first, then the combination of claims 4 and 7 establish that the central region of the first strand comprises the sequence complementary to the target RNA.
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 § 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.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (US 9725715 B2, published 8/8/2017) in view of Kaemmerer (US 20100063134 A1, published 3/11/2010).
Regarding claim 1-3, Han teaches signal activatable molecule constructs for delivery of molecules and related components having a 17 to 30 bp targeting domain duplex RNA (see abstract), wherein the complex comprises a 17 to 30 bp targeting domain duplex RNA having a guide strand complementarily bound to a passenger strand and a sensor strand (see claim 1-18, 21, and Fig. 3). Han teaches where the passenger strand is covalently attached at its 5’ end to the 3’ end of at least one protection strand and at its 3’ to 5’ end of the at least one protection strand, such that the passenger strand and protection strand together constitutes a single continuous strand (see claim 1, Han).
Han teaches where the protection segment of the at least one protection strand is complementarily bound to at least one displacement segment of a sensor strand to form a 14 to 30 bp sensor domain duplex polynucleotide (see claims 1 and 2, Han). Han further teaches that the sensor strand further comprises at least one toehold segment (which comprises an overhang, see Fig. 18A-C, column 2) presented for binding to a signal molecule and that in the activated confirmation, the sensor strand is bound to the signal molecule and is detached from the at least one protection strand and from the targeting domain (see claim 1, Han).
Han further teaches that upon binding of the signal molecule to the toehold segment, the displacement segment is displaced from the protection segment, the sensor strand forms a sensor strand-signal molecule complex detached from the targeting domain, and the targeting domain is allowed for processing by Dicer and/or an Argonaute enzyme (see column 3, line 30).
Han also teaches methods of treating a disease in an individual through signal activated molecular delivery in cells (see column 6) and where exemplary targeting domains in the sense of the present disclosure comprise siRNA, saRNA, microRNA, and additional polynucleotides identifiable by a skilled person (see column 17).
Regarding claims 1-3, Han does not teach where the method of modulating a target RNA is in the nervous system of a subject, or a method to treat a neurological disease or disorder, or where the target RNA is a nervous system-specific RNA.
Regarding claims 1 and 2, Kaemmerer discloses a method of modulating a target RNA in the nervous system of a subject by surgically implanting a catheter so that a discharge portion of the catheter lies adjacent to a predetermined infusion site in a brain, and discharging through the discharge portion of the catheter lies adjacent to a predetermined infusion site in a brain, and discharging through the discharge portion of the catheter a predetermined dosage of at least one substance capable of inhibiting production of at least one neurovegetative protein by brain infusion of small interfering RNA (see abstract, paragraph 0002). Kaemmerer teaches administering a nucleic acid complex, the nucleic acid complex comprising a first nucleic acid duplex, wherein the complex comprises a first nucleic acid duplex with a sequence complementary to a target RNA (see paragraph 0002 and 0056) wherein the target RNA or protein expression from the target RNA is reduced by at least 30% in a subject to treat the neurological disease or disorder (By the term “inhibit” or “inhibitory” it is meant that the activity of the target genes or level of mRNAs or equivalent RNAs encoding target gene is reduced below that observed in the absence of the provided small interfering RNA. Preferably the inhibition is at least…50% less…than in the absence of the small interfering RNA (see paragraph 0045 and 0108).
Regarding claim 3, Kaemmerer teaches methods for delivering small interfering RNA to targeted sites in the brain to inhibit or arrest the development and progression of neurodegenerative disorders (see paragraph 0003).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to administer the signal-activatable construct of Han according to the methods of treating a neurological disease according to Kaemmerer, wherein the targeting domain of Han is directed towards a nervous-system specific RNA.
One would expect a reasonable chance of success as Kaemmerer establishes RNAi-mediated knockdown of nervous system targets is therapeutically desirable and that oligonucleotide agents can be delivered to act with regions of the nervous system. Han teaches a conditional activatable RNAi construct which a skilled artisan would expect predictable results if used with the methods of Kaemmerer as a substitution to improve a similar method for silencing CNS targets. Furthermore, Han already contemplates the use of the presented RNAi constructs for treating a disease.
One would be motivated to do so as Han addresses a recognized deficiency of constitutively active RNAi agents by activating RNAi activity based off the detection of an input transcript, therefore offering greater control to when RNAi is induced, in order to ensure controlled delivery to specific environments, such as specific cell types and or tissues of individuals (see background of Han). One would be further motivated to treat a neurodegenerative disease, as disclosed in Kaemmerer.
In view of the foregoing, claims 1-3 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claims 1-16, 20-21, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (US 9725715 B2, published 8/8/2017) in view of Kaemmerer (US 20100063134 A1, published 3/11/2010).
Regarding claims 1-3, the method of modulating a target RNA in the nervous system of a subject or method of treating a neurological disease or disorder comprising administering a nucleic acid complex, wherein the target RNA is a nervous-system specific RNA is taught by the Han and Kaemmerer, as described above.
Regarding claim 4-5, Han teaches a targeting domain duplex RNA which comprises a 17 to 30 bp construct with a guide strand complementarily bound to a passenger strand (see abstract). A guide strand forms a sequence that is complimentary to the target RNA.
Regarding claim 6, Han teaches where the passenger strand comprises a blocker domain to provide the polynucleotide with exonuclease resistance (see column 33, line 50), wherein the phosphorothioate segment of the blocker domain comprises at least one to five nucleotides linked by phosphorothioate linkages to form a phosphorothioate sequence having a 5’ and a 3’ end, and attaching at the 5’ end the first end of the non-nucleic acid polymer segment through a phosphodiester linkage (see column 35, line 44, claim 5 and 8).
Regarding claim 7, Han teaches where the first strand comprises 17 to 30 bp, a second nucleic acid strand binding to a central region of the first nucleic acid strand to form a duplex, and a third nucleic acid strand binding to a 5’ and 3’ region of the first nucleic acid strand to form a second duplex (see Figs. 9A-D, 12A-B, and column 3 and 4).
Regarding claim 8, Han teaches wherein the first nucleic acid duplex comprises a sequence complementary to the target RNA (see abstract, and Figs. 9, 12-17, wherein the guide or targeting RNA strand comprises overhangs, evidenced by Figs. 9, 12-17. Therefore, the targeting domain of the duplex is where the first and second strand complement and forms the “central” region (where the duplex is formed, not comprising the overhangs). The term central is broad and applicant defines it briefly in Design 2, Fig. 1 (instant drawings) which shows the core region formed by the passenger strand and guide strand being complemented.
Regarding claims 9 and 10, Han teaches wherein the central region of the first nucleic acid strand is linked to the 5’ region of the first nucleic acid strand via a 5’ connector, the central region of the first nucleic acid strand is linked to the 3’ region of the first nucleic acid strand via a 3’ connect, or both (see Figs. 9, 12-17, wherein the first nucleic acid strand is linked to another region of the first strand via a C3 linker, indicated by L2L5’ or L2L3’). While the instant application recites “connector”, the instant specification discloses the connector can be a three-carbon linker (see paragraph 0119 of the instant specification).
Regarding claim 11, Han teaches wherein the connector comprises a 2’-O-methyl RNA (see Figs. 9, 12-17).
Regarding claim 12, Han teaches where the duplex formed by the guide strand and the passenger strand has a blunt end at the 3’ end of the guide strand (see column 50).
Regarding claim 13, Han teaches signal activatable molecule constructs for delivery of molecules and related components having a 17 to 30 bp targeting domain duplex RNA (see abstract), wherein the complex comprises a 17 to 30 bp targeting domain duplex RNA having a guide strand complementarily bound to a passenger strand and a sensor strand (see claim 1-18, 21, and Fig. 3). Han teaches where the passenger strand is covalently attached at its 5’ end to the 3’ end of at least one protection strand and at its 3’ to 5’ end of the at least one protection strand, such that the passenger strand and protection strand together constitutes a single continuous strand (see claim 1, Han).
Han teaches where the protection segment of the at least one protection strand is complementarily bound to at least one displacement segment of a sensor strand to form a 14 to 30 bp sensor domain duplex polynucleotide (see claims 1 and 2, Han). Han further teaches that the sensor strand further comprises at least one toehold segment (which comprises an overhang, see Fig. 18A-C, column 2) presented for binding to a signal molecule and that in the activated confirmation, the sensor strand is bound to the signal molecule and is detached from the at least one protection strand and from the targeting domain (see claim 1, Han).
Han teaches two protection arms present on the 5’ and 3’ end of the passenger strand, however, contemplates a single protection strand being bound to the sensor strand, as evidenced by claim 1. Under the broad interpretation of claim 1, which 13 depends on, the passenger strand can be considered the “first” strand, where the sensor strand binds only to one end of the passenger strand, that being the portion with the protection strand. Furthermore, claim 13 does not include any limitation wherein the first strand is required to be complementary to the target RNA.
Regarding claim 14, Han teaches where 17 to 30 bp targeting domain duplex RNA having a guide strand complementarily bound to a passenger strand (see abstract, claim1-18 and 21, and Fig. 3).
Regarding claim 15, Han teaches where the sensor duplex can vary from 12 to 30 bp, possibly 14 to 30 bp or 16 to 30 bps (see column 30, line 58).
Regarding claim 16, Han teaches wherein the central region of the first nucleic acid strand is linked to the 5’ region of the first nucleic acid strand via a 5’ connector, the central region of the first nucleic acid strand is linked to the 3’ region of the first nucleic acid strand via a 3’ connect, or both (see Figs. 9, 12-17, wherein the first nucleic acid strand is linked to another region of the first strand via a C3 linker, indicated by L2L5’ or L2L3’) (see Fig. 12A below where the first nucleic acid strand is linked to another region of itself through linkers, indicated by L1L5’ and L1L3’).
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Regarding claim 20, Han teaches that the sensor strand further comprises at least one toehold segment (which comprises an overhang, see Fig. 18A-C, column 2) presented for binding to a signal molecule and that in the activated confirmation, the sensor strand is bound to the signal molecule and is detached from the at least one protection strand and from the targeting domain (see claim 1, Han).
Han further teaches that upon binding of the signal molecule to the toehold segment, the displacement segment is displaced from the protection segment, the sensor strand forms a sensor strand-signal molecule complex detached from the targeting domain, and the targeting domain is allowed for processing by Dicer and/or an Argonaute enzyme (see column 3, line 30). Furthermore, Fig. 18A-C discloses the toehold of the third strand has an overhang of 8 modified nucleotides.
Regarding claim 21, Han teaches wherein the 5’ toehold segment and/or 3’ toehold segment comprise a blocker (see claim 8) providing the toehold segment with exonuclease activity. The toehold segment is present on the sensor or third strand (see claim 1).
Regarding claim 24, Han teaches where the targeting domain duplex RNA from 19 to 21 bp of the 5’ terminus of the guide strand and passenger strand are protected by base modifications described in the present disclosure to minimize occurrence of processing of the construct in an inactive conformation (see column 31, line 50). Furthermore, Han teaches where modified bases can be used throughout the complexes to increase thermodynamic stability and nuclease resistance, decrease toxicity, and/or increase specificity (see column 32, line 40).
Regarding claims 1-16, 20-21, and 24, Han does not specifically teach where the first nucleic acid strand comprises the sequence complementary to the target RNA, making it the guide RNA strand (as recited in claim 4 and 8).
It would have been obvious to one skilled in the art to modify the small conditional RNA complex of Han to arrive at the instantly claimed invention. Regarding claims 1 and 2, the instant claims are broad to the structure of the instant composition. Applicant recites a first nucleic acid duplex formed by a first and second strand wherein the first nucleic acid duplex comprises a sequence complementary to a target RNA. In view of the art of Han (US 9725715 B2), Han proposes a target domain RNA duplex comprising a guide and passenger strand. The guide or passenger strand could be labeled as either the first strand or the second strand, given the broad nature of claim 1, and the first duplex would have a sequence complementary to target RNA. Han then teaches where the sensor strand binds to the passenger strand (See Fig. 9, 12-17), but as explained, the passenger strand of Han could be considered the “first” strand, which would address the limitations of claim 1. It is not until claims 4 and 8, where the applicant introduces a limitation that a portion of the first nucleic acid strand (claim 4) or the central region of the first nucleic acid strand (claim 8) comprises the sequence complementary to the target RNA. Claim 4 and 8 defines the first strand of the nucleic acid complex as the guide strand, evidenced by Fig. 3 of the instant application, which is not explicitly taught by Han. Han discloses a Guide – Passenger – Sensor strand orientation (See Figs. 9, 12-17), not a Passenger – Guide – Sensor orientation.
However, Han discloses all the structural elements of the instant application, such as the use of siRNA and miRNA in the guide, a sensor strand which has overhangs, a guide strand which targets the target RNA, and a passenger strand which supports the construct, as well as the use of linkers and nucleotide modifications. As the claims recite assigned functional roles amongst the three strands, the identifiable alternatives are finite and disclosed through Han. As Han already teaches a sensor strand bound to a passenger strand, the only other alternative is a sensor strand bound to a guide strand, as recited in the instant application.
When a person of ordinary skill has good reason to pursue the known options within his or her technical grasp, and the number of identified, predictable solutions is small, pursuit of the known options is not innovation but ordinary skill and common sense. See KSR rationales, MPEP § 2143(I)(E). In the present case, Han teaches conditional activation of an RNAi complex allows for enhanced control over RNAi property, and Kaemmerer’s active agent lacks, wherein the use of Han’s agents would yield an improvement and predictable results in Kaemmerer’s methods. Furthermore, one seeking control of RNAi expression in the nervous system would have had good reason to test alternative constructs of Han, which would include only a small number of arrangements between the guide, passenger, and sensor strand.
In view of the foregoing, claims 1-16, 20-21, and 24 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Claims 1, 27-28, 40, 42-45, 47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Han et al. (US 9725715 B2, published 8/8/2017) in view of Kaemmerer (US 20100063134 A1, published 3/11/2010), Khvorova et al. (US 20160355808 A1, published 12/8/2016) and Das et al. (WO 2019/033079 A1, published 2/14/2019), further evidenced by Aguiar et al. (RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA, Translational Neurodegeneration, Volume 6, Issue 30, all pages, published 11/27/2017).
Regarding claim 1, the method of modulating a target RNA in the nervous system of a subject comprising administering a conditional nucleic acid complex is described in the combined arts of Han and Kaemmerer, as described above.
Regarding claim 27, Kaemmerer teaches where the present invention provides methods to deliver small interfering RNA vectors to the human central nervous system and thus treat neurodegenerative diseases by reducing the production of a pathogenic protein within neurons (see paragraph 0108 of Kaemmerer).
Regarding claim 28, Kaemmerer teaches a method (medical system, see claim 1) for treating a neurodegenerative disease (which comprises administering RNAi to the nervous system), wherein the predetermined location of the medical system is the cerebral cortex (see claim 12), the striatum (see claim 13), or the cerebellar cortex (see claim 14).
Regarding claim 40, Han teaches where the nucleic acid complex is siRNA (see column 40, line 20, Figs. 3A-B), which targets or silences mRNA, and Kaemmerer teaches where the medical system, comprising small interfering RNA, is complementary to the mRNA for alpha-sy-nuclein (see claim 16, Kaemmerer) or BACE1 (see claim 17, Kaemmerer).
Regarding claim 42, Kaemmerer teaches the method of modulating the expression or production of protein in neurons by intracranial delivery of small interfering RNA (claim 28), wherein the neurodegenerative disorder is Parkinson’s disease (see claim 41), Alzheimer’s disease (see claim 42), or Huntington’s disease (see claim 43). While Kaemmerer does not teach specifically targeting the HTT gene, a skilled artisan would recognize that Huntington’s disease is a disorder caused by CAG repeats within the HTT gene. This is evidenced by Aguiar et al. (RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA, Translational Neurodegeneration, Volume 6, Issue 30, all pages, published 11/27/2017), wherein Aguiar teaches shRNA targeting the HTT gene associated with Huntington’s disease, as well as disclosing that siRNA has been used in the past (see abstract of Aguiar). As Kaemmerer discloses an identical target disorder, a skilled artisan would recognize that the siRNA of Kaemmerer would target the HTT gene. Furthermore, Khvorova teaches SEQ ID NO: 124 which targets the HTT gene in Huntingtin’s disease.
Regarding claims 45, Han teaches activatable RNA complexes, as described in the rejection of claim 1, wherein the sensor strand comprises overhangs that can bind a signal molecule. Han defines a signal molecule as “a signal polynucleotide” (see column 41, line 31). Han defines where a signal molecule can also comprise other molecules known to bind aptamers, wherein aptamers indicate oligonucleic acid that bind a specific target. Han discloses that the various molecular targets can be small molecules, proteins, nucleic acids, and even cells, tissues, and organisms (see column 41, line 35).
Regarding claim 47, Han teaches activatable RNA complexes, as described in the rejection of claim 1, wherein the sensor strand comprises overhangs that can bind a signal molecule. Han defines a signal molecule as “a signal polynucleotide” (see column 41, line 31). Looking to the instant specification for guidance, applicant discloses a “universal” mRNA that is not cell-type selective as microRNA (miRNA), such as miR-133b (see paragraph 0154 of the instant specification). Han teaches where the signal polypeptide used in the experiment is expected to be a short oligonucleotide or RNA segment, such as a miRNA (see column 40, line 38).
Regarding claim 49, Han teaches where a method for treating disease in an individual through signal activated molecular delivery in cells, and related compositions and systems, are described. The related pharmaceutical composition comprises one or more signal activatable constructs herein described, and in particular one or more of the molecular complexes, activatable molecular complex, activated complexes and/or exonuclease resistant complexes herein described, with a pharmaceutical acceptable vehicle (see column 6, line 52). Furthermore, Kaemmerer, which specifically discloses siRNA for targeting the nervous system, discloses the composition comprising the siRNA agents is formulated in accordance with standard procedure as a pharmaceutical composition adapted for delivered administration to human beings or other mammals (see paragraph 0096).
Regarding claims 43-44, the combined teachings of Han and Kaemmerer does not teach wherein the third nucleic acid strand comprises SEQ ID NO: 17 or 18, wherein the second nucleic acid strand comprises any one of SEQ ID NOs: 2, 19, and 20, and/or the first strand comprises SEQ ID NO: 1.
Regarding claim 43, Das teaches conditional siRNAs wherein the nucleic acid complex comprises a guide, core, and sensor strand (see paragraph 0010). Das further teaches SEQ ID NO: 1 which is described as a sensor strand, shown below.
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Following alignment (shown below), SEQ ID NO: 1 shows 100% identity across the 22-mer region, with the exception that the instant SEQ ID NO: 17 has 3 modified Uracil, indicated as Thymine. However, Han already discloses that the sensor strand can comprise modifications, not limited to LNA modifications and/or 2’-O-methyl bases in order to optimize balance between toxicity, leakage, and cost (see column 38, line 59). Therefore, a skilled artisan would be motivated to modify the sensor strand of SEQ ID NO: 1 disclosed in Das to obtain a sequence which comprises the sensor or third strand of SEQ ID NO: 17 of the instant application.
Regarding claim 44, Khvorova teaches RNA molecules (e.g. siRNAs) that target Huntingtin target sequences (see paragraph 0009). Khvorova further teaches SEQ ID NO: 124, shown below, which has 100% identity with SEQ ID NO: 1 of the instant application, however, with modified uracils (shown below). A skilled artisan would recognize that modification of Uracil to Thymine to increase or enhance stability of the RNA structure is very routine and well known in the art.
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It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Han, Kaemmerer, Khvorova, and Das to arrive at the instantly claimed invention.
Regarding composition of the instant invention, applicant only broad describes a first, second, and third strand. If applicant intends to disclose the first strand as the guide strand, the second strand as a scaffolding passenger strand, and a third strand as the sensor strand, a skilled artisan would arrive at that orientation wherein the sensor strand binds the guide strand through routine experimentation with a predictable outcome, as described above.
One would expect a reasonable chance of success as Han discloses conditional RNAs activated by a signal polypeptide for the delivery of RNA interference and Kaemmerer discloses where RNA interference, such as siRNAs, can be used for modulating the expression of target mRNAs in the nervous system to treat neurodegenerative diseases. Han broadly describes where a guide strand is complementary to a target mRNA, which can encompass any target region of any gene. While Han and Kaemmerer does not teach the specific SEQ ID NOs claimed, Khvorova teaches SEQ ID NO: 124 which comprise a sequence of 100% identity to SEQ ID NO: 1, aside from routine modifications of U to T, for oligonucleotides (including siRNA) to target the HTT gene associated with Huntingtin’s disease. Therefore, the target of SEQ ID NO: 1 of the instant application was already known in the art, at the time of filing. Das discloses small conditional, activatable RNAs, wherein the sensor strand comprises SEQ ID NO: 1. SEQ ID NO: 1 comprises a sequence with 100% identity, aside from well-known and routine U to T modifications, with SEQ ID NO: 17 of the instant application. Furthermore, looking at the instant specification for guidance, applicant discloses the nucleic acid strands comprise of the core nucleic acid strand, the passenger nucleic acid strand, and the sensor nucleic acid strand (see paragraph 0170). In view of the inventor’s prior art in both Han and Das, a skilled artisan would recognize that the “third strand” of the instant invention corresponds and serves the same function as SEQ ID NO: 124 of Das, which is already disclosed in the prior art before the time of filing.
One would be motivated to do so as Han addresses a recognized deficiency of constitutively active RNAi agents by activating RNAi activity based off the detection of an input transcript, therefore offering greater control to when RNAi is induced, in order to ensure controlled delivery to specific environments, such as specific cell types and or tissues of individuals (see background of Han). One would be further motivated to treat a neurodegenerative disease, as disclosed in Kaemmerer, wherein the disease is Huntingtin’s disease, as disclosed by the target mRNA of Khvorova.
In view of the foregoing, claims 1, 27-28, 40, 42-45, 47, and 49 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
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.
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Claims 1-16, 20-21, 24, 27-28, 40, 42-45, and 47-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 21 of U.S. Patent No. 9, 725,715 B2 in view of Kaemmerer (US 20100063134 A1, published 3/11/2010), Khvorova et al. (US 20160355808 A1, published 12/8/2016) and Das et al. (WO 2019/033079 A1, published 2/14/2019).
Claim 21 of the issued patents depends on the composition presented in claim 1, wherein the construct is drawn to a conditional RNA-complexes, which comprises a guide strand, core strand, and sensor strand. Other elements including blockers and other moieties are further described in the claims of the issued patent. However, claim 21 of the issued patent broadly recites “a method for targeting a disease-associated gene through enzyme-assisted signal activated molecular delivery in cells in vitro”.
Regarding the instant application, it would have been obvious to modify the RNA complex of the issued patent with the siRNA of Khvorova to target the HTT gene as Kaemmerer describes siRNA targeting the nervous system of a subject for the treatment of Huntingtin’s while Khvorova teaches SEQ ID NO: 124 which comprises a sequence of 100% identity to SEQ ID NO: 1. Furthermore, Das discloses activatable RNA complexes with a sensor strand comprising SEQ ID NO: 1 which comprises SEQ ID NO: 17 of the instant application, wherein a skilled artisan would recognize that substitutions of equivalent structures would yield predictable results.
A skilled artisan would have been motivated to do so to treat a neurodegenerative disease, wherein the disease is Huntingtin’s disease, as disclosed by the teachings of Khvorova and Kaemmerer.
Claims 1-16, 20-21, 24, 27-28, 40, 42-45, and 47-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16 of U.S. Patent No. 11643659 B2 in view of Han et al. (US 9725715 B2, published 8/8/2017), Kaemmerer (US 20100063134 A1, published 3/11/2010) and Khvorova et al. (US 20160355808 A1, published 12/8/2016).
Claim 16 of the issue patent recites a method of treating acute myeloid leukemia (AML) comprising administration of a therapeutically effective amount of conditional RNA-sensor complex of claim 1. Claim 1 of the issued patent and dependent claims describe a composition that is identical to that of the instant application, absent evidence to the contrary.
Claim 16 of the issued patent does not recite a method to modulate nervous system RNA or target a neurodegenerative disease. However, Kaemmerer teaches siRNA used to target neurodegenerative diseases and Khvorova teaches SEQ ID NO: 124, which comprises a sequence with 100% identity to SEQ ID NO: 1 of the instant application. Han describes conditional RNA complexes that is identical in structure to that of the issued patent and pending instant application, wherein the RNA complexes can be used to broadly treat a disease, absent evidence to the contrary.
Therefore, a skilled artisan would recognize that the substitution of the nucleic acid strand targeting a gene associated with a neurodegenerative disease, such as Huntingtin’s disease, instead of a strand that targets AML, would result in predictable outcomes, such as the treatment of a disease or modulation of a target mRNA.
Claims 1-16, 20-21, 24, 27-28, 40, 42-45, and 47-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 19 of U.S. Patent No. US 12385041 B2 in view of Han et al. (US 9725715 B2, published 8/8/2017), Kaemmerer (US 20100063134 A1, published 3/11/2010) and Khvorova et al. (US 20160355808 A1, published 12/8/2016).
Claim 19 of the issued patent recites a method of treating a pathological condition comprising administering a therapeutically effective amount of a conditional RNA-sensor complex of claim 1. Claim 1 recites a conditional sensor RNA-complex that is identical to that of the instantly claimed administered composition.
While claim 19 of the issued patent does not recite a method of modulating nervous system RNA or treating a neurodegenerative disease, the instant claims are patentably indistinct in view of Kaemmerer and Khvorova. Both Kaemmerer and Khvorova teach the use of siRNA to modulate nervous system mRNA or to target a neurodegenerative disease. Han describes conditional RNA complexes that is identical in structure to that of the issued patent and pending instant application, wherein the RNA complexes can be used to broadly treat a disease, absent evidence to the contrary.
Therefore, a skilled artisan would recognize that the substitution of the nucleic acid strand targeting a gene associated with a neurodegenerative disease, such as Huntingtin’s disease, instead of a strand that targets a gene associated with myocardial infraction, would result in predictable outcomes, such as the treatment of a disease or modulation of a target mRNA.
Conclusion
No claims are allowed.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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