DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-18 are examined on the merits.
Priority
This application is a national stage application, which claims
priority from U.S. Provisional Application 63488057, filed 03/02/2023 is
acknowledged.
Claim Objections
Claim 1 is objected to because of the following informalities: reciting an abbreviation without spelling out what the abbreviation is in the first occurrence in the claim set (PPAR γ).
Claim 3 is objected to because of the following informalities: The phrase “the therapeutic agent to for down-regulating CCL20”, contains the words “to for” which renders the claim grammatically incorrect.
Claim 9 is objected to because of the following informalities: The phrase “the therapeutic agent to for down-regulating chemokine ligand 20 (CCL20)”, contains the words “to for” which renders the claim grammatically incorrect.
Claim 11 is objected to because of the following informalities: The phrase “the therapeutic agent to for down-regulating chemokine ligand 20 (CCL20)”, contains the words “to for” which renders the claim grammatically incorrect.
Claim 12 is objected to because of the following informalities: The phrase “the therapeutic agent to for down-regulating chemokine ligand 20 (CCL20)”, contains the words “to for” which renders the claim grammatically incorrect.
Claim 13 is objected to because of the following informalities: The phrase “the therapeutic agent to for down-regulating chemokine ligand 20 (CCL20)”, contains the words “to for” which renders the claim grammatically incorrect.
Claim 14 is objected to because of the following informalities: The phrase “the therapeutic agent to for down-regulating chemokine ligand 20 (CCL20)”, contains the words “to for” which renders the claim grammatically incorrect.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0023] states, “brain sections stained for GFAP (astrocytes, green) and DAPI (blue, cell nuclei).” The colors cannot be seen in the black and white drawings.
Appropriate correction is required.
Note that 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. 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).
The use of the terms FLUORO-JADE (e.g., paragraphs [0014], [0015], [0081], [0087] and [0089]), and ALEXA FLUOR (paragraph [0083]), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever 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 Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1: The phrase “to inhibit chemokine ligand 20 (CCL20) and/or chemokine receptor 6 (CCR6) one of a dendrimer nanoparticle complexed with at least one short hairpin RNA (shRNA)-encoding DNA plasmid of at least one dendriplex, or a PPAR𝛾 agonist” is structurally incoherent and grammatically vague. The claim transitions from indicating the biological targets (CCL20, CCR6) to listing a specific composition (“ one of a dendrimer nanoparticle”) without proper transitional language. Because of this grammatical gap the physical relationship between the inhibition mechanism and the dendrimer nanoparticle in indefinite.
Furthermore, the phrase “one of a dendrimer nanoparticle complexed with at least one short hairpin RNA (shRNA)-encoding DNA plasmid of at least one dendriplex”. The insertion “of at least one dendriplex” is confusing, as a dendriplex is inherently the complex formed by the dendrimer and nucleic acids. It is unclear if the plasmid belongs to a separate dendriplex, or if the dendrimer nanoparticle itself must be a component of a larger dendriplex.
Claims 2-18 depend from claim 1 and are rejected for the same reasons applied to claim 1.
Claim 3: The claim refers to “one of a dendrimer nanoparticle complexed with at least one short hairpin RNA (shRNA)-encoding DNA plasmid of at least one dendriplex”. The insertion “of at least one dendriplex” is confusing, as a dendriplex is inherently the complex formed by the dendrimer and nucleic acids. It is unclear if the plasmid belongs to a separate dendriplex, or if the dendrimer nanoparticle itself must be a component of a larger dendriplex.
Claim 7: “The method of claim 1, wherein the or a pharmaceutically acceptable salt thereof, is grammatically incorrect and lacks antecedent basis and structural coherence. It is unclear what the term “the” refers to, as no antecedent noun or phrase is provided between the limitation. What feature is being modified by “a pharmaceutically acceptable salt therefor”, as the claim does not identify the underlying compound or agent.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 7-18 are rejected under 35 U.S.C. 103 as being unpatentable over Amanipour et al. (“Amanipour”, Conf Proc IEEE Eng Med Biol Soc. 2016) in view of Mohapatra et al. (Mohapatra”, US 2015/0030609 A1), Hauser. T. (“Hauser”, US 9.200,276 B2) and Gu et al. (“Gu”, Materials Science and Engineering, 2017) and Kimbrel et al. (“Kimbrel”, US 2021/0182552 A1).
For the purposes of this rejection, claim 1 is interpreted as requiring the administration of therapeutic amount of a therapeutic agent to inhibit chemokine ligand 20 (CCL20) and/or chemokine receptor 6 (CCR6) ; and a therapeutic amount of stem cells. For the purposes of this rejection, claim 7 is incomplete and is interpreted as being drawing to the steps of claim 1.
Regarding claims 1-2, Amanipour teaches that mild traumatic brain injury (mTBI) could cause hearing loss at high frequencies, as shown in “Fig. 1”. After trauma, noticed notable changes in threshold data in comparison to baseline level (e.g., paragraph 5th, left column, page 1855; Fig.1).
Amanipour does not teach administration of a therapeutic agent to inhibit chemokine ligand 20 or chemokine receptor 6 in the form of shRNA. Amanipour does not teach a dendrimer nanoparticle complexed with shRNA-encoding DNA plasmid. Amanipour does not teach administering a therapeutic amount of stem cells, as required by the instant claims. However, this is cured by Mohapatra, Hauser, Gu and Kimbrel.
Mohapatra teaches the use of CC chemokine ligand 20 (CCL20), as a novel biomarker for early detection of traumatic brain injury (TBI) and/or neurodegeneration in the brain. Treatment methods for traumatic brain injury by modulating systemic and/or brain-specific CCL20- CCR6 signaling.(e.g., paragraph 0006). Mohapatra teaches method for treating traumatic brain injury and/or neurodegeneration in the brain, wherein the method comprises reducing CCL20 expression by introducing into a cell an antisense molecule against CCL20 (e.g., paragraph 0115). Mohapatra teaches the therapeutic agent treating TBI and/or neurodegeneration in the brain is a siRNA having a sequence sufficiently complementary to a targetCCR6 mRNA sequence to direct target-specific RNA interference (RNAi). A method for treating traumatic brain injury and/or neurodegeneration in the brain, wherein the method comprises reducing CCR6 expression by introducing into a cell an antisense molecule against CCR6 (e.g., paragraph 0116). Mohapatra teaches vectors ( e.g., viral vectors) and expression constructs comprising the nucleic acid molecules useful for inhibiting CCL20 expression and/or activity (e.g., paragraph0127). Mohapatra teaches therapeutic compositions that contain a therapeutically effective amount of the therapeutic agent of the subject invention and a pharmaceutically acceptable carrier or adjuvant (e.g., paragraph 0146). Mohapatra teaches The compositions of the subject invention can be administered to the subject being treated by standard routes, including oral, inhalation, or parenteral administration
including intravenous, into a subject (e.g., paragraph 0155). Mahapatra teaches the therapeutic or pharmaceutical compositions of the subject invention can also be formulated as neutral or salt forms (e.g., paragraph 0154).
Hauser teaches methods of inhibiting gene expression using the oligo
nucleotides of the invention may be combined with other knockdown and knockout methods, e.g., gene targeting, antisense RNA, ribozymes, double-stranded RNA (e.g., shRNA and siRNA) to further reduce expression of a target gene. (e.g., line 61, column 24).
Gu teaches a polyamidoamne dendrimer functionalized graphene oxide (GO-PAMAM) was designed, which could load doxorubicin (DOX) and MMP-9 shRNA plasmid at the same time in order to achieve effective treatment to breast cancer (e.g., abstract).
Kimbrel teaches preparations of the subject mesenchymal stromal cells (MSCs) are useful in the treatment of pathologies, including unwanted immune responses, e.g., autoimmune diseases and disorders, as well as inflammatory diseases and disorders (e.g., paragraph 0008). Kimbrel teaches the pharmaceutical preparation may comprise an amount of mesenchymal stromal cells effective to treat a disease or condition selected from the group consisting of hearing loss (e.g., paragraph 0194). Kimbrel teaches The MSCs of the instant invention may be administered
using modalities known in the art including, but not limited to, injection via intravenous, intramyocardial, transendocardial, intravitreal, or intramuscular routes or local implantation dependent on the particular pathology being treated (e.g., paragraph 0250).
Based on these teachings, it would have been prima facie obvious to
one of ordinary skill in the art, before the effective filing date of the claimed
invention, to combine the teachings of Amanipour -traumatic brain injury (mTBI) could cause hearing loss, with the teachings of Mohapatra -a method for treating traumatic brain injury by inhibiting the pro inflammatory molecules CCL20 or CCR6 expression through the use of a vector encoding siRNA directed against CCL20 and/or CCR6, with the teachings of Hauser -shRNA expression constructs for silencing genes, with the teachings of Gu -dendrimer nanoparticles can be complexed with shRNA-encoding plasmid for intracellular delivery of the shRNA-plasmid, and the teachings of Kimbrel -mesenchymal stromal cells effective to treat a disease such as hearing loss; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method for treating a hearing disorder by administering dendrimer nanoparticle complexed with shRNA CCL20 or shRNA-CCR6 encoding plasmid and a therapeutic mesenchymal stromal cells.
One of ordinary skill in the art before the effective filing date of the
invention would have been motivated to combine these teachings to reduce the inflammation through CCL20/CCR6 inhibition, by improving the intracellular delivery of inhibitory shRNA and promoting the regeneration of damaged tissue with reasonable expectation of improving the recovery from traumatic brain injury-induced auditory disfunction.
Regarding claims 9-11, the prior art combination establishes both components of these claims: Mohapatra teaches the administration of the CCL20/CCR6 down-regulating agent and Kimbrel teaches the administration of the therapeutic stem cells. The dependent claims adds a chronological limitation: administering the therapeutic agent before, concurrently or after administering the cellular therapy. The therapeutic order or timing of administering two therapeutic agents in a combination protocol is generally consider a matter of routine optimization for a person of ordinary skill in the art. Choosing to administer a molecular-down regulating agent prior, after, or concurrently to introducing stem cells is one of a limited number of predictable options available for a combination treatment.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Amanipour et al. (“Amanipour”, Conf Proc IEEE Eng Med Biol Soc. 2016) in view of Mohapatra et al. (Mohapatra”, US 2015/0030609 A1), Hauser. T. (“Hauser”, US 9.200,276 B2) and Gu et al. (“Gu”, Materials Science and Engineering, 2017), Kimbrel et al. (“Kimbrel”, US 2021/0182552 A1) as applied to claims 1-4, 8-18 above, and further in view of Qi et al. (“Qi”, Int J Clin Exp Med., 2010).
Amanipour, Mohapatra, Hauser, Gu and Kimbrel do not teach PPAR agonist for treatment for auditory dysfunction, as required by the instant claims. However, this is cured by Qi.
Qi teaches the beneficial effects of PPAR-γ activation in traumatic brain injury (TBI) appear to be mediated through downregulation of inflammatory responses, reduction of oxidative stress, inhibition of apoptosis, and promotion of neurogenesis (e.g., abstract). Qi teaches TBI initiates an acute inflammatory response, which involves the integrated activities of cytokines, chemokines, vascular adhesion molecules,
and inflammatory cells (e.g., paragraph 2nd, right column, page 2). Qi teaches PPAR-γ plays a major role in the regulation of inflammatory responses. Increasing evidence has shown that PPAR-γ activation mitigates inflammation associated with chronic and acute neurological insults (e.g., paragraph 3rd, right column, page 2). Qi teaches antidiabetic
drugs known as thiazolidinediones (i.e., rosiglitazone, pioglitazone, troglitazone and ciglitazone) mediate their therapeutic effects
through the interaction with PPAR-γ (e.g., paragraph 2nd, left column, page 2).
Based on these teachings, it would have been prima facie obvious to
one of ordinary skill in the art, before the effective filing date of the claimed
invention, to combine the teachings of Amanipour, Mohapatra, Hauser, Gu and Kimbrel - a method for treating a hearing disorder by administering dendrimer nanoparticle complexed with shRNA CCL20 or shRNA-CCR6 encoding plasmid and a therapeutic mesenchymal stromal cells, with the teachings of Qi – benefits of PPAR-γ activation in traumatic brain injury mediates through downregulation of inflammatory responses with the PPAR gamma agonists rosiglitazone, pioglitazone, troglitazone and ciglitazone; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method for treating a hearing disorder by administering dendrimer nanoparticle complexed with shRNA CCL20 or shRNA-CCR6 encoding plasmid a therapeutic mesenchymal stromal cells and a PPAR-γ agonist.
One of ordinary skill in the art before the effective filing date of the
invention would have been motivated to combine these teachings to reduce the inflammation through CCL20/CCR6 inhibition, promoting the regeneration of damaged tissue and use of PPAR-γ agonist to improve the recovery from traumatic brain injury-induced auditory disfunction.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights