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 .
Applicants' arguments, filed 04/27/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 28, 30, 31, 35, 36, 38, 47-49 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) an “administering” step—instructing a doctor to administer the miR-195-p5 to his patient—(2) a “determining” step—telling the doctor to measure the resulting metabolite levels, i.e. miR-195-5p and/or fragments thereof, in the patient's blood—and (3) a “correlating/wherein” step—listing risk factors, i.e. cognitive impairment, associated with levels of miR-195-5p. This judicial exception is not integrated into a practical application because limiting drug administration to this patient population does no more than simply refer to the relevant pre-existing audience of doctors who used miR-195 to treat patients suffering from cognitive impairment. The combination amounts to nothing significantly more than instructing doctors to apply the applicable laws when treating their patients. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because measuring metabolite levels of miR-195 is a well-understood, routine conventional activity previously engaged by others in the neurodegenerative field. See Kassab et al. (below) teaching treatment of Alzheimer’s disease with microRNA, Keuren-Jensen et al. teaching methods for the diagnosis and prognosis of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease by measuring microRNA in the patient, and Ohlmeyer et al. teaching compounds useful to treat cognitive impairment.
Claim Rejections - 35 USC § 102/103
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.
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.
Claim(s) 10, 21, 22, 25, 46 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Kassab et al., (US 2020/0071699).
Kassab et al. teaches, “Treatment of Alzheimer’s disease with microRNA and ghrelin”, wherein a product for treating Alzheimer’s disease “includes recombinant adeno-associated virus (rAAV) vectors containing at least one microRNA (miRNA) sequence”, wherein at least one miRNA sequence is selected from the group consisting of . . . miR-195” (Abstract; clm. 10, 21-22, 25, 46).
Note: Applicant’s specification, Alzheimer’s disease is characterized by tau hyperphosphorylation (see Spec at p. 19, line 13-15).
miR-195 is typically used as a broader term or alias for miR-195P, which is the guide strand derived from the miR-195 hairpin precursor. Accordingly, it would have been obvious or expected to use the main functional mature miR-195-5p in the method of Kassab et al. Kassam et al. further teaches, “equivalents may be substituted for elements thereof” (p. 12, para. [0094]) making obvious the use of miR-195-5p would qualify as a mimic or variant of miR-195.
“In an exemplary embodiment of a method of treating Alzheimer’s disease of the present disclosure, the step of administering is performed using intranasal administration” (p. 2, para. [0026]).
The prior art is anticipatory insofar as it teaches intranasal administration to a subject in need thereof a therapeutically effective amount of a composition comprising miR-195.
Assuming, purely arguendo, that the prior art does not provide sufficient specificity to give rise to anticipation, it would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to administer a therapeutically effective amount of miR-195-5p to a subject in need thereof.
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.
1) Claim(s) 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kassab et al., (US 2020/0071699) as applied to claim 10 above, and further in view of Hao et al. (International Journal of Molecular Medicine, 2020).
Kassab et al., which is taught above, differs from claim 26 insofar as it does not teach the sequence number for miR-195.
Hao et al. provides the sequence for “miR-195 mimic” as “5'-UAGCAG CACAGAAAUAUUGGC-3'’, as per SEQ ID 1.
Accordingly, it would have been expected or obvious to a person having ordinary skill in the art at the time of applicant’s filing to use 5'-UAGCAG CACAGAAAUAUUGGC-3 as the miR-195 mimic in the method of Jing et al.
2) Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kassab et al., (US 2020/0071699) as applied to claim 10 above, and further in view of Ohlmeyer et al. (WO 2019/104041, cited in IDS).
Kassab et al., which is taught above, differs from claim 27 insofar as it does not teach a compound selected from the group.
Ohlmeyer et al. teaches compounds “used to treat cognitive impairment or traumatic brain injury, including promoting regeneration in cases of traumatic brain injury, or for treating neurogenerative disorders” (Abstract).
Suitable compounds include:
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(p. 40, Claim 8).
Generally, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition that is to be used for the very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. See MPEP 2144.06.
Accordingly, it would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to administer the compounds of Ohlmeyer et al. in the method of Kassab et al. since the patient population of Kassab et al. includes those with a neurogenenerative disorder, i.e., Alzheimer’s disease, and the compounds of Ohlmeyer et al. treat neurogenenerative disorders.
3) Claim(s) 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kassab et al., (US 2020/0071699) as applied to claim 10 above, and further in view of Ramos-Cejuda et al., (EBioMedicine, 2018).
Kassab et al., which is taught above, differs from claim 45 insofar as it does not teach where the disease is traumatic brain injury.
Ramos-Cejuda et al. teaches, “Cerebrovascular pathology, a key element in both conditions [traumatic brain injury (TBI) and Alzheimer’s disease (AD)], could represent a mechanistic link between Aβ/tau deposition after TBI and the development of post concussive syndrome, dementia and chronic traumatic encephalopathy” (CTE) (Abstract) and “TBI-induced neurovascular injuries accelerate amyloid β (Aβ) production and perivascular accumulation, arterial stiffness, tau hyperphosphorylation and tau/Aβ-induced blood brain barrier damage, giving rise to a deleterious feed-forward loop” (Id.). These injuries are described as “AD-like” (Id.)
Because the symptoms of TBI are like Alzheimer’s disease, including amyloid β (Aβ) production and tau hyperphosphorylation, it would have been reasonable to include TBI patients with AD-like symptoms in the patient population of Kassab et al.
Accordingly, it would have been obvious to a person having ordinary skill in the art to treat patients with traumatic brain injury in the method of Kassab et al. because they present with the same or similar symptoms of Alzheimer’s patients. Established precedent states, “when there is a motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1390.
4) Claim(s) 10, 24 and 46 is/are rejected under 35 U.S.C. 103 as obvious over Jing et al., (CN111249235, cited in IDS) in view of Islam et al., (Molecules 2020).
Jing et al. teaches, “A brain targeted nanoliposome loaded with a positively charged polymer/miR-195 complex and its preparation method and application” (p. 1 of Translation), wherein the nanoliposome is used “to treat Alzheimer’s disease and vascular dementia, in particular to cognitive dysfunction caused by Alzheimer disease and cerebral ischemia” (Abstract).
Note: Applicant’s specification, Alzheimer’s disease is characterized by tau hyperphosphorylation (see Spec at p. 19, line 13-15).
miR-195 is typically used as a broader term or alias for miR-195P, which is the guide strand derived from the miR-195 hairpin precursor. Accordingly, it would have been obvious to use the main functional mature miR-195-5p in the method of Jing et al. It is further noted that Jing et al. teaches, “the nucleic acid sequence of miR-195 is one of miR-195 mimics, modified miR-195 mimics or miR-195 precursor mimics” (p. 6, 5th paragraph). Accordingly, miR-195-5p would qualify as a mimic or variant of miR-195.
“Pharmacodynamic evaluation showed that the liposome could significantly improve the learning and memory ability of bilateral common carotid artery ligation-induced vascular dementia in rats and APP/PS1 and miR-195 knockout mice” (p. 11, 1st paragraph).
“Any modification or equivalent replacement of the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention should be included in the present invention, within the scope of protection” (p. 12, 3rd paragraph).
The nanoliposome is a type liposome, and a nanoparticle, as per claims 24.
Jing et al. does not teach that the nanoliposomes are administered intranasally.
Islam et al. teaches intranasal delivery of nanoformulations for treating neurological disorders, such as “Alzheimer’s disease” (see Abstract). Nanoformulations include “Lipid Nanoparticles” (p. 13, sec. 7.3).
“The intranasal route offers many advantages and can hence overcome some of the limitations; it is thus a preferred, alternative drug administration rout over the parenteral and oral routes” (p. 16, Conclusion).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to administer the nanoformulations of Jing et al. intranasally since intranasal administration offers “many advantages” and is preferred over parenteral and oral routes, as taught by Islam. The artisan would have had a reasonable expectation of success with the method insofar as the method considers lipid nanoparticles and patients with Alzheimer’s disease.
4) Claim(s) 28, 30-31, 35-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Keuren-Jensen et al., (US 2014/0303025, cited in IDS) in view of Kassab et al., (US 2020/0071699) and/or Jing et al., (CN111249235, cited in IDS).
Keuren-Jensen et al. teaches methods for the diagnosis and prognosis of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. The method makes “determinations regarding the potential severity of pathologies associated with neurodegenerative disorders by determining whether a plurality of miRNAs has deregulated biological expression in a sample from the subject” (Abstract). By “measuring the expression of a plurality of microRNAs from a biological sample from the subject” Alzheimer’s disease can be diagnosed (p. 1, para. [0003]).
Patient samples, for measuring a plurality of microRNAs, include “cerebrospinal fluid” (p. 3, para. [0017]) and “serum” (p. 3, para. [0018]), as per claim 28(a). The plurality of microRNAs include “miR-195-5p” (Id. para. [0021]), as per claim 28(b).
In Alzheimer’s disease “there is a need to assess the miRNA content in CSF and serum (SER) form subjects with full neuropathological evaluations and to identify those miRNA with deregulated expression levels that correlate with the presence and severity of neurodegenerative disease” (p. 1, para. [0007]).
In regard to step (c) of claim 28, the prior art teaches, “Alternatively, the difference in expression may be qualitative, e.g., in that expression is modulated, up-regulated, resulting in an increased amount of transcript, or down-regulated, resulting in a decreased amount of transcript” (p. 5, para. [0048]) and “Typically the level of the miRNA in a biological sample obtained from the subject is different (e.g., increased) form the level of a healthy individual” (Id. para. [0049]). Accordingly, it would have been obvious to compare levels of miR-195 to a control sample (e.g., healthy subject) to determine need for treatment of Alzheimer’s disease based on the differences in the levels of microRNA.
Keuren-Jensen et al. includes a treatment option (see p. 5, para. [0046]; p. 9, para. [0088]-[0089]), but does not teach step (d), administering a therapeutically effective amount of miR-195 to a subject in need thereof.
Kassab et al. teaches, “Treatment of Alzheimer’s disease with microRNA and ghrelin”, wherein a product for treating Alzheimer’s disease “includes recombinant adeno-associated virus (rAAV) vectors containing at least one microRNA (miRNA) sequence”, wherein at least one miRNA sequence is selected from the group consisting of . . . miR-195” (Abstract; clm. 31, 36).
Jing et al. teaches, “A brain targeted nanoliposome loaded with a positively charged polymer/miR-195 complex and its preparation method and application” (p. 1 of Translation), wherein the nanoliposome is used “to treat Alzheimer’s disease and vascular dementia, in particular to cognitive dysfunction caused by Alzheimer disease and cerebral ischemia” (Abstract; claim 35).
Again, miR-195 is typically used as a broader term or alias for miR-195P, which is the guide strand derived from the miR-195 hairpin precursor. Accordingly, it would have been obvious or expected to use the main functional mature miR-195-5p in the method of Kassab et al. Kassab et al. further teaches, “equivalents may be substituted for elements thereof” (p. 12, para. [0094]) making obvious the use of miR-195-5p would qualify as a mimic or variant of miR-195, as per claim 31.
“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)” (see MPEP 2144.07).
In this case it was known to administer therapeutically effective amounts of miR-195 to Alzheimer’s patients as a treatment option, in view of Kassab et al. or Jing et al.
Accordingly, it would have been obvious to administer miR-195 to Alzheimer’s patients in the method of Keuren-Jensen et al. since miR-195 administration was known for treating Alzheimer’s disease, as taught by Kassab et al. The artisan would have had a reasonable expectation of success with the combination insofar as Keuren-Jensen et al. teaches, “Treatment of a condition or disease is the practice of any method, process, or procedure with the intent of halting, inhibiting, slowing or reversing the progression of a disease, disorder or condition, substantially ameliorating clinical symptoms of a disease, disorder or condition, up to and including returning the diseased entity to its condition prior to development of the disease” (p. 9, para. [0089]).
5) Claim(s) 38, 47-48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Keuren-Jensen et al., (US 2014/0303025, cited in IDS) in view of Kassab et al., (US 2020/0071699) and/or Jing et al., (CN111249235, cited in IDS) as applied to claim 28 above, and further in view of Ohlmeyer et al. (WO 2019/104041, cited in IDS).
The combination of Van Keuren-Jensen et al., Kassab et al., (US 2020/0071699) and/or Jing et al., which is taught above, differs from claim 38, 47-48 insofar as it does not teach a compound from the group.
Ohlmeyer et al. teaches compounds “used to treat cognitive impairment or traumatic brain injury, including promoting regeneration in cases of traumatic brain injury, or for treating neurogenerative disorders” (Abstract).
Suitable compounds include:
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(p. 40, Claim 8).
Generally, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition that is to be used for the very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. See MPEP 2144.06.
Accordingly, it would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to administer the compounds of Ohlmeyer et al. in the method of Van Keuren-Jensen et al. and Kassab et al. since the patient population of Van Keuren-Jensen et al and Kassab et al. includes those with a neurogenenerative disorder, i.e., Alzheimer’s disease, and the compounds of Ohlmeyer et al. treat neurogenenerative disorders.
7) Claim(s) 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Keuren-Jensen et al., (US 2014/0303025, cited in IDS) in view of Kassab et al., (US 2020/0071699) and/or Jing et al., (CN111249235, cited in IDS) as applied to claim 28 above, and further in view of Fowler et al., (Adv Drug Deliv Rev. 2020).
The combination of Van Keuren-Jensen et al., Kassab et al., (US 2020/0071699) and/or Jing et al., which is taught above, differs from claim 38, 47-48 insofar as it does not teach intrathecal administration.
Fowler et al. teaches, in the art of intrathecal drug delivery, which is the administration of substances into the cerebrospinal fluid (CSF)” (Abstract). Further, “nanomedicine systems” could offer a solution to “inadequate delivery to tissue or cellular targets” (Id.). “In contrast to the fate of freely administered drugs, nanomedicine systems can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents within the CNS” (Id.).
Fowler et al. recognizes the clinical use of “nanoparticles”, “liposomes” (Id) and “adeno-associated viral vectors” (p. 12, 1st paragraph) for intrathecal purposes (Id).
Accordingly, it would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to administer the nanoliposomes of Jing et al. and/or viral vectors of Kassab et al. intrathecally since both are recognized as suitable forms of nanomedicine systems cable of can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents, via intrathecal administration, within the CNS, as taught by Fowler et al.
Technological Background
The prior art made of record and considered pertinent to applicant's disclosure Chakraborty et al. (US 2014/0147454). Chakraborty et al. is pertinent for teaching compositions and methods for the manufacture and optimization of modified mRNA molecules (Abstract). The reference teaches “miR-195-3P” and “miR-195-5p” (p. 18, para. [0165]), quantification of mRNA from “peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid . . .” (p. 40, para. [0287]).
Response to Arguments
Applicant’s arguments with respect to claims have been considered but are moot in view of the new ground of rejection.
Conclusion
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER E WEBB whose telephone number is (571)270-3287 and fax number is (571) 270-4287. The examiner can normally be reached from Mon-Fri 7-3:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Walter E. Webb
/WALTER E WEBB/Primary Examiner, Art Unit 1612
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