DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of SEQ ID NO: 131 in the reply filed on August 6 2026 is acknowledged. The traversal is on the ground(s) that the claims share a common inventive concept directed to treatment of pulmonary disease through NOX4 inhibition. It is argued that the Aissaoui reference is small-molecule. This is not found persuasive because as established in the restriction requirement, unity is lacking as the specifical technical feature (NOX4 inhibition) does not make a contribution over the prior art as NOX4 inhibitors were known. While Aissaoui teaches small molecules claim 1 is generic to the form of any inhibitor, which includes small molecules. Furthermore, in the references cited below NOX4 antisense oligonucleotide inhibitors were known and thus these compounds do not make a contribution over the prior art.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-8, 24-25, 30-40, 43-44, 47-49 and 51-53 are pending in the application. In light of the discovered prior art, the species election of SEQ ID NO: 131 is expanded to include the antisense oligonucleotides of Kalinski et al. and Dusting et al. Accordingly, claims 1-8, 24-25, 30-40, 43-44, 47-49 and 51-53 are being examined on the merits herein.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a 371 of PCT/US2022/035735 (06/30/2022) which claims benefit of 63/217,542 (07/01/2021) as reflected in the filing receipt issued on February 4 2025.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 13 2024 and June 2 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 39 is objected to because of the following informalities: The acronym “MOE” is not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “MOE” is interpreted to mean 2’-O-methoxyethyl. Appropriate correction is required.
Claim 49 is objected to because of the following informalities: The acronym “RNAi”, “RISC” and “Ago2” are not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “RNAi” is interpreted to mean 2’-O-methoxyethyl is interpreted to mean RNA interference; “RISC” is interpreted to mean RNA-induced silencing complex and “Ago2” is interpreted as Argonaut 2. Appropriate correction is required.
Claim Rejections - 35 USC § 112-Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-8, 24-25, 30-40, 43-44, 47-49 and 51-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating chronic obstructive pulmonary disease (COPD) or pulmonary hypertension (PH) with a NOX-4 inhibitor, does not reasonably provide enablement for treating all pulmonary diseases or disorders in a subject having or at risk of having a pulmonary disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and Nature of the Invention
The claim is very broad insofar as it recites treating any pulmonary disease or disorder with any NOX4 inhibitor.
The Relative Skill Level, the State of the Prior Art and The Level of
Predictability in the Art
The relative skill of those in the art is high, that of an MD or PHD someone with experience in not only in chemistry and molecular biology but also treatment of pulmonary diseases.
As illustration of the state of the art the examiner directs attention to Li et al. (Cellular Physiology, 2020). Li et al. is directed to the role of NOX4 in pulmonary diseases. It is stated that the signaling pathways associated with NOX4 are complicated. Negative and positive feedback play significant roles in regulating NOX4 expression. The role of NOX4 is controversial because NOX4 plays a protective or damaging role in different respiratory diseases (abstract). Li et al. teaches that some evidence demonstrates that NOX4 plays a protective role in endothelial cells through the NOX4/Nrf2 signaling pathway. This signaling pathway is one of the most significant protective pathways in the respiratory system (page 1631). Li et al. teaches that NOX4 is involved in PAH and promotes pulmonary artery smooth muscle proliferation, endothelial cell migration, and pulmonary vascular wall thickening, resulting in vascular remodeling, vascular stenosis, and plaque formation in the pulmonary artery (section 3.3). Li et al. confirms that increases in NOX4 and ROS levels enhance inflammation and alveolar description. Specifically discussing the connection between NOX4 and COPD (section 3.4). Hendricks et al. (Front. Cell. Infect. Microbiol., 2022) teaches that endothelial NOX4 oxidase negatively regulates inflammation and improves morbidity during influenza A virus lung infection in mice. In summary they found that NOX4 is protective against inflammatory and ischemic stress and that endothelial NOX4 ameliorates some symptoms of IAV infection (page 9, last paragraph).
The amount of direction or guidance provided and the presence or absence of working examples
Example 3/7 of the specifications shows that the modified oligonucleotides/RNAi agents were effective in a short-term cigarette smoke model of COPD.
Example 4/8-9 of the specification shows that modified oligonucleotides/RNAi agents were effective in a Sugen 5416/hypoxia-induced mouse model of pulmonary hypertension.
But does not teach that the instantly claimed inhibitors can be used in any pulmonary disease as contemplated by the claims and does not teach how it can be used in pulmonary diseases to which NOX4 has been shown to provide a protective effect against.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to treat any pulmonary disease as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-8, 24 and 51 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kalinski et al. (USPGPUB No. 20100273854).
The instant application claims a method of treating a pulmonary disease or disorder in a subject having, or at risk of having, a pulmonary disease or disorder comprising administering a NOX4-specific inhibitor to the subject, thereby treating the pulmonary disease or disorder in the subject. The pulmonary disease or disorder is chronic obstructive pulmonary disease (COPD) or pulmonary hypertension (PH).
Kalinski et al. is directed to compositions and methods for inhibiting NADPH oxidase expression. Claimed is a method of treating a subject in need of treatment for a disease or condition selected from hearing loss, acute renal failure, nephritis, ocular disease, Acute Respiratory Distress Syndrome and other acute lung injuries, lung transplantation, spinal cord injury, pressure sores, osteoarthritis and Chronic Obstructive Pulmonary Disease (COPD), comprising administering to the subject a compound in an amount effective to treat the disease or condition (claim 22). Wherein COPD is one of three specific conditions (claim 29). Example 4 is directed to model systems of chronic obstructive pulmonary disease (COPD). The compound as claimed is a double-stranded siRNA which comprises an antisense sequence to an mRNA transcribed from mammalian gene of NOX4(claim 1) wherein the preferred gene is NOX4 (paragraph 0042). Preferred NOX4 siRNA (paragraph 0166) compounds are taught in Table A:
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. COPD is characterized mainly by emphysema (example 4).
Therefore, Kalinski et al. anticipates claims 1-2 by teaching treating COPD with NOX4 siRNA (NOX4-specific inhibitor). Kalinski et al. expressly claims administration of the siRNA to a subject in need of treatment. One skilled in the art would immediately envision treating COPD as example 4 is directed to treating COPD and as claimed is one of three different conditions. Therefore, one skilled in the art would immediately envision treating COPD. MPEP 2131.
Regarding claims 3-7, Kalinski et al. teaches that COPD is mainly characterized by emphysema. Thus, the treatment of COPD as taught in example 4 would be in treating emphysema which would fall within the scope of difficulty breathing, improves breathing, lung function and improves lung function.
Regarding claim 8, Kalinski et al. teaches that in a preferred embodiment the cell is a human cell (paragraph 0130); preferred embodiments are subject being treated is a warm-blooded animal and in particular mammals including human (paragraph 0158).
Regarding claim 24, Kalinski et al. teaches a siRNA which is an antisense agent.
Regarding claim 51, Kalinski et al. claims an effective amount is administered. Kalinski et al. teaches that methods of the invention comprise administering to the patient one or more inhibitory compounds which down-regulate expression of a NOX gene (e.g. NOX4) and in particular siRNA in a therapeutically effective dose, so as to thereby treat the patient (paragraph 0052; 0204-0205)
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 25, 31-32, 35, 43-44, 49 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Kalinski et al. as applied to claims 1-8, 24 and 51 above.
Applicant Claims
The NOX4-specific inhibitor is an antisense agent comprising a modified oligonucleotide, wherein the modified oligonucleotide has a nucleobase sequence complementary to any one of SEQ ID Nos: 1-5.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Kalinski et al. are set forth above. Kalinski et al. teaches a double-stranded siRNA which is used in treating COPD. The claimed double-stranded siRNA may be modified or unmodified in its sugar residue (claim 1). The modification can be at the 2’ position of the sugar residue (claim 11) and includes a methoxy (2’-O-methyl) (claim 13). Kalinski et al. teaches that it will be readily understood by those skilled in the art that the compounds of the present invention consist of a plurality of modified and/or unmodified ribonucleotides, which are linked through covalent linkages. Each such covalent linkage may be a phosphodiester linkage, a phosphorothioate linkage, or a combination of both, along the length of the ribonucleotide sequence of the individual strand (paragraph 0116).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kalinski et al. teaches siRNA which target NOX4 and suggests the nucleotides can be modified, Kalinski et al. does not expressly teach the NOX4 siRNA are modified.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize modification on the siRNA targeting NOX4 taught in Kalinski et al. One skilled in the art would have been motivated to utilize modifications as Kalinski et al. teaches that it will be readily understood by those skilled in the art that the compounds of the present invention consist of a plurality of modified and/or unmodified ribonucleotides, which are linked through covalent linkage and each such covalent linkage may be a phosphodiester linkage, a phosphorothioate linkage, or a combination of both. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
Regarding claim 25, as shown in the alignment below NOX4 siRNA #55 of Kalinski et al. has 100% complementary identity to instant SEQ ID NO: 2:
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Regarding claim 31, the siRNA is double-stranded.
Regarding claim 32, the exemplified siRNA consist of 19 linked nucleosides.
Regarding claim 49, Kalinski et al. teaches RNA interference (RNAi) is based on the ability of dsRNA species to enter a cytoplasmic protein complex, where it is then targeted to the complementary cellular RNA and specifically degrade it. The RNA interference response features an endonuclease complex containing an siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having a sequence complementary to the antisense strand of the siRNA duplex (paragraph 0087).
Regarding claim 52, Kalinski et al. teaches that the composition for use in the novel treatments of the present invention may be formed as aerosols (paragraph 0207).
Claims 52-53 rejected under 35 U.S.C. 103 as being unpatentable over Kalinski et al. 1-8, 24, 31-32, 35, 43-44, 49 and 51-52 above and in view of Francois et al. (USPGPUB No. 20140371133)
Applicant Claims
The instant application claims the inhibitor is administered by aerosolized delivery. The instant application claims the inhibitor is administered via a nebulizer or inhaler.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Kalinski et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kalinski et al. teaches treating COPD with a NOX4 inhibitor and that administration can be with aerosols, Kalinski et al. does not expressly teach a nebulizer or an inhaler. However, this deficiency is cured by Francois et al.
Francois et al. is directed to methods of treating chronic disorders with complement inhibitors. It is taught that a variety of different devices are available for respiratory administration. Nebulizers are devices that transform solutions or suspensions of medications into aerosols that are suitable for deposition in the lower airway. A metered dose inhaler (MDI) is a handheld aerosol device that uses a propellant to deliver the therapeutic agent. A dry powder inhaler (DPI) is a breath-actuated device that delivers the drug in the form of particles contained in a capsule or blister that is punctured prior to use and typically does not employ a propellant. Examples of DPIs currently used to deliver medications for treating asthma and/or COPD include, e.g., Diskus, Aerolizer, HandiHaler, Twisthaler, Flexhaler (paragraph 0333).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
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 Kalinski et al. and Francois et al. and utilize a conventional device for respiratory administration. One skilled in the art would have been motivated to utilize a nebulizer, a metered dose inhaler or a dry powder inhaler as these are well-known devices available for respiratory administration as taught by Francois et al. There is a reasonable expectation of success as Kalinski et al. teaches aerosol administration and Francois et al. teaches nebulizers and metered dose inhalers are aerosol devices and these are used to deliver medications for treating COPD.
Claims 1-8, 24-25, 30-32, 43-44, 48 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Dusting et al. (USPGPUB No. 20070037883) in view of Hollins et al. (Respiratory Research, 2016).
Applicant Claims
The instant application claims a method of treating a pulmonary disease or disorder in a subject having, or at risk of having, a pulmonary disease or disorder comprising administering a NOX4-specific inhibitor to the subject, thereby treating the pulmonary disease or disorder in the subject. the pulmonary disease or disorder is chronic obstructive pulmonary disease (COPD) or pulmonary hypertension (PH).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Dusting et al. is directed to therapeutic compositions. Claimed is an isolated cell-impermeable compound which inhibits an NADPH oxidase activity in a particular cell wherein said NADPH oxidase comprises an extracellular NADPH binding domain (claim 1). As claimed, the compound inhibits or reduces the generation of superoxide, hypochlorite, lipid peroxides, peroxynitrite, hydrogen peroxide and/or hydroxyl radicals (claim 1). The compound binds to a nucleic acid molecule comprising a nucleotide sequence set forth in SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:5 or SEQ ID NO:7 or a nucleotide sequence having at least about 60% identity thereto or its complementary form or a nucleotide sequence capable of hybridizing to SEQ ID NO:1 or SEQ ID NO:3 or SEQ ID NO:5 or SEQ ID NO:7 or a complementary form thereof under low stringency conditions (claim 16). SEQ ID NO: 1 is the nucleotide sequence encoding human NOX 4 (paragraph 0050). SEQ ID NO: 3 is the nucleotide sequence encoding mouse NOX 4 (paragraph 0051). Compound which inhibit NADPH oxidase include antisense oligonucleotides, sense oligonucleotides or full-length sense nucleic acid molecules useful in inducing cosuppression or other RNAi (RNA interference) mediated gene silencing events (paragraph 0014). According to the invention compounds include antisense oligomeric compounds, antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, alternate splicers, primers, probes, and other oligomeric compounds which hybridize to at least a portion of the target nucleic acid. As such, these compounds may be introduced in the form of single-stranded, double-stranded, circular or hairpin oligomeric compounds. Once introduced to a system, the compounds of the invention may elicit the action of one or more enzymes or structural proteins to effect modification of the target nucleic acid. One non-limiting example of such an enzyme is RNAse H, a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are “DNA-like” elicit RNAse H. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression. (paragraph 0109). Preferred forms of antisense compounds is single-stranded antisense oligonucleotides (paragraph 0110). Oligonucleotides refer to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimics, analogs etc. This term includes naturally occurring nucleobases, sugars and covalent internucleoside backbone linkages as well as non-naturally occurring portions (paragraph 0111). Length of oligonucleotides include about 8 to about 80 nucleobases (paragraph 0113). Preferred modified oligonucleotide backbones include phosphorothioate (paragraph 0119). It is taught that gene silencing is accomplished by providing oligonucleotides which specifically hybridize with one or more nucleic acid molecules encoding NOX4 (paragraph 0103). Shown in Table 7 is an antisense oligonucleotide of SEQ ID No: 17.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Dusting et al. teach antisense oligonucleotide which inhibit or reduce reactive oxygen species production in cells, Dusting et al. does not expressly teach treating a pulmonary disease such as COPD. However, this deficiency is cured by Hollins et al.
Hollins et al. is directed to airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD. It is taught that the burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD). Taught is that the findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and ROS were reduced markedly by NOX4 inhibition supporting a potential role for NOX4 in COPD (abstract; page 4, left column).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 1-2, 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 Dusting et al. and Hollins et al. and administer the NOX4 inhibitors of Dusting et al. to a subject with COPD. One skilled in the art would have been motivated to administer the NOX4 inhibitors to this patient population as Hollins et al. teaches that increased NOX4 expression is associated with COPD and that inhibition reduces reactive oxygen species. There is a reasonable expectation of success as Dusting et al. teaches the inhibitors can be used in methods for reducing ROS production in cells.
Regarding claims 3-7, these claims recite the effect achieved following administration. Since it is obvious to administer the inhibitors to a patient with COPD, ameliorating one of the claimed symptoms is obvious. Furthermore, Dusting et al. teaches treating lymphedema (claim 24) which reads on edema symptoms as well as abnormal oxygen flow (claim 23).
Regarding claim 8, Dusting et al. claims the mammal is human.
Regarding claim 24-25, Dusting et al. expressly teaches a NOX4 antisense oligonucleotide of SEQ ID No: 17 which has 100% complementary identity with instant SEQ ID NO: 2 (shown below).
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As taught by Dusting et al., the nucleic acid molecule may also be modified (claim 28), specifically teaching that oligonucleotides includes naturally occurring nucleobases, sugars and covalent internucleoside backbone linkages as well as non-naturally occurring portions. It is taught that such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as enhanced cellular uptake, enhanced affinity for a target nucleic acid and increased stability. (paragraph 0111).
Regarding claims 30-31, firstly SEQ ID No: 17 (above) is single stranded. Dusting et al. teaches that compounds may be introduced in the form of single-stranded or double-stranded oligonucleotides.
Regarding claim 32, SEQ ID NO: 17 consists of 20 linked nucleotides. Modification is obvious for the reasons set forth above.
Regarding claims 43-44, Dusty et al. teaches that preferred antisense compounds contain modified backbones. Preferred modified backbones include phosphorothioate (paragraph 0118-0119). It would have been obvious to one of ordinary skill in the art to try any of the specifically taught modified backbones as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding claim 48, Dusty et al. teaches that once introduced to a system, the compounds of the invention may elicit the action of one or more enzymes or structural proteins to effect modification of the target nucleic acid. One non-limiting example of such an enzyme is RNAse H, a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are “DNA-like” elicit RNAse H. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression. (paragraph 0109).
Regarding claim 51, Dusty et al. teaches the terms “effective amount” or “therapeutically effective amount” of an agent as used herein are meant a sufficient amount of the agent to provide the desired therapeutic effect. Furthermore, an “effective Nox4-inhibiting amount” or “an effective NADPH oxidase inhibiting amount” of an agent is a sufficient amount of the agent to at least partially inhibit or ameliorate the symptoms mediated or caused by ROS production. Administering to a mammal an effective amount of a compound is taught (paragraph 0042; 0126).
Claims 33-40 and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Dusting et al. in view of Hollins et al. as applied to claims 1-8, 24-25, 30-32, 43-44, 48 and 51 above and in further view of Prakash et al. (USPGPUB No. 20140343123) and GenBank (NCBI Reference Sequence: NM_001285833.1, June 30 2020).
Applicant Claims
As elected the inhibitor is SEQ ID NO: 131 which is a 3-10-3 cEt modified gapmer with uniform phosphorothioate internucleoside linkages.
The instant application claims wherein at least on nucleoside of the modified oligonucleotide comprises a modified nucleobase which is specifically claimed as a 5-methyl cytosine.
The instant application claims the modified oligonucleotide comprises a modified sugar moiety and specific modifications include bicyclic sugar moiety such as cEt or non-bicyclic sugar moieties such as 2’-F, 2’-OMe or 2’-MOE sugar moiety.
The instant application claims the modified oligonucleotide has: a gap segment consisting of linked 2'-deoxynucleosides;a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar moiety.
The instant application claims the antisense agent comprises a conjugate group.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Dusting et al. and Hollins et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Dusting et al. teaches compounds which are antisense compounds for inhibiting NOX4 and teaches that it is known the art that single-stranded antisense compounds which are “DNA-like” elicit RNAse H and activation of RNase H results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression, Dusting et al. does not expressly teach a gapmer and a NOX4 sequence which would result in instant SEQ ID NO: 131. However, this deficiency is cured by Prakash et al. and GenBank.
Prakash et al. is directed to conjugated antisense compounds and their use. It is taught that the principle behind antisense technology is that an antisense compound hybridizes to a target nucleic acid and modulates the amount, activity, and/or function of the target nucleic acid. An example of modulation of RNA target function by degradation is RNase H-based degradation of the target RNA upon hybridization with a DNA-like antisense compound. Another example of modulation of gene expression by target degradation is RNA interference (RNAi). RNAi refers to antisense-mediated gene silencing through a mechanism that utilizes the RNA-induced silencing complex (RISC) (paragraph 0003). The oligonucleotides are gapmers which comprise two external regions or “wings” and a central or internal region or “gap” (paragraph 3097). The 5’-wings of a gapmer can contain a bicyclic nucleoside (paragraph 3099) or non-bicyclic modified nucleosides (paragraph 3100) same with the 3’-wind (paragraph 3105; 3106). Antisense compound taught include those with the following pattern: kkkddddddddddkkk (table 2) wherein “k” indicates a cET bicyclic nucleoside and “d” indicates a DNA (deoxyribonucleoside) (paragraph 3564). It is taught that in some embodiments the oligonucleotide is uniformly linked by phosphorothioate internucleoside linkages (page 3120). Taught is a conjugated antisense compounds. Conjugates such as GalNAc have been used to facilitate uptake of certain compound and conjugates are attached to single-stranded antisense compounds, including, but not limited to RNase H based antisense compounds (paragraphs 0007-0009). Non-bicyclic modifications include 2’-OMe and 2’-MOE (paragraph 3103). Gapmers include 3-10-3; 5-10-5, etc. (table 16). Taught is that the nucleobase sequence comprising at least 16 nucleobase portion complementary to an equal length portion of a target nucleic acid (embodiment 170). Modified nucleobases include 5-methyl cytosine and in some embodiment some, all or none of the cytosine moieties in an oligonucleotide are 5-methyl cytosine moieties (paragraph 3126).
GenBank teaches the mRNA sequence of Mus musculus NADPH oxidase 4 (Nox4), transcript variant 2. This mRNA sequence has 100% identity to instant seq ID No: 2. (see attached GenBank which contains the alignment of instant SEQ ID NO: 2 and NOX4 mRNA variant 2).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
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 Dusting et al., Hollins et al., Prakash et al. and GenBank and utilize a gapmer as the antisense oligonucleotide. One skilled in the art would have been motivated to utilize a gapmer as Dusting et al. suggests that single-stranded antisense compounds which are “DNA-like” elicit RNAse H can be utilized and Prakash et al. teaches gapmers are DNA-like antisense compounds. Since the antisense compounds are taught as being capable of hybridizing to a target nucleic acid to modulate the activity, one skilled in the art would have been motivated to utilize gapmers to target NOX4 as Dusting et al. teaches antisense compounds of NOX4.
Regarding the elected compound, Dusting et al. suggests the oligonucleotide can bind to NOX4 target RNA which includes mouse NOX4. Genbank teaches that NCBI Reference Sequence: NM_001285833.1 (Mouse NOX4) has a sequence which as shown above has 100% identity with instant SEQ ID NO: 2. Therefore, based on the teachings of Dusting et al. and Prakash et al., one skilled in the art would have been motivated to design antisense oligonucleotides which target any portion of the target mRNA. Both Dusting et al. and Prakash et al. suggest lengths which overlap with the instant claims with Prakash et al. specifically teaching a 3-10-3 or 16 length nucleobase which is complementary to an equal length portion of a target nucleic acid. As shown below instant SEQ ID NO: 131 has 100% complementary identity with mouse NOX4 mRNA.
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Prakash et al. expressly teaches a gapmer pattern of kkkddddddddddkkk wherein “k”indicates a cET bicyclic nucleoside and “d” indicates a DNA (deoxyribonucleoside).
Regarding the claimed modifications in claims 33-39 and 43-44, Prakash et al. teaches modifications include 5-methylcytosine, all phosphorothioate, bicyclic cET as well as non-bicyclic modifications such as 2’-OMe and 2’-MOE. Phosphorothioates improve stability (paragraph 3341); 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 Dusting et al., Hollins et al., Prakash et al. and GenBank and utilize any of the specifically taught modifications. It would have been obvious to one of ordinary skill in the art to try any of the specifically taught modifications as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). Furthermore, Dusting et al. teaches that modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as enhanced cellular uptake, enhanced affinity for a target nucleic acid and increased stability. (paragraph 0111). This provides the motivation to manipulate the type and number of modifications in order to achieve the desired properties.
Regarding claim 37, Prakash et al. teaches as used herein, “constrained ethyl nucleoside” or “cEt” means a nucleoside comprising a bicyclic sugar moiety comprising a 4′-CH(CH3)—O-2′ bridge (paragraph 2967).
Regarding claim 40, Prakash et al. teaches the same structure for gapmers.
Regarding claim 47, Prakash et al. teaches a conjugate attached to a gapmer to facilitate uptake. 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 Dusting et al., Hollins et al., Prakash et al. and GenBank and utilize a conjugate in order to facilitate uptake as taught by Prakash et al.
Claims 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Dusting et al. in view of Hollins et al. as applied to claims 1-8, 24-25, 30-32, 43-44, 48 and 51 above and in further view of Francois et al.
Applicant Claims
The instant application claims the inhibitor is administered by aerosolized delivery. The instant application claims the inhibitor is administered via a nebulizer or inhaler.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Dusting et al. and Hollins et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Aerosolized or nebulizer or inhaler are not expressly taught. However, this deficiency is cured by Francois et al.
The teachings of Francois et al. are set forth above.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
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 Dusting et al., Hollins et al. and Francois et al. and utilize a conventional device for respiratory administration. One skilled in the art would have been motivated to utilize a nebulizer, a metered dose inhaler or a dry powder inhaler as these are well-known devices available for respiratory administration as taught by Francois et al. There is a reasonable expectation of success as Francois et al. teaches nebulizers and metered dose inhalers are aerosol devices and these are used to deliver medications for treating COPD.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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